Clinical trial NCT02915835
Conditions: Scleroderma Digital Ulcers
Keywords: Scleroderma Digital Ulcer
Sponsor: Dinesh Khanna, MD, MS
Start date: 2016-09-01; Completion date: 2018-07-24
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to provide preliminary data on the efficacy (digital ulcer net burden) and safety of riociguat administered 3 times daily (TID) in comparison to placebo in patients with scleroderma-associated digital ulcers

Detailed description:
This clinical trial is a US, multicenter, double-blind, randomized placebo-controlled, parallel- group study with a total of 20 participants planned to be randomized (approximately 10 participants to the riociguat group and 10 to the placebo group). In addition, a standardized wound care protocol will be followed by the investigators and digital photography will be taken of the cardinal ulcer.

The study will allow standard of care medications for the management of DU as background therapy. These may include calcium channel blockers, low dose aspirin, angiotensin enzyme inhibitors, etc. and will be determined by the participant's local physician.

The study design consists of three phases:

* Screening phase: up to 2 weeks
* Double-blind Treatment phase: 16 weeks of double-blind treatment, consisting of:
* Dose titration period of up to 8 weeks, and
* Stable dosing period of up to 8 weeks
* Open-label Extension phase for participants with active DU at the end of the double- blind treatment phase or development of an active DU within a month of completing double-blind phase, consisting of:
* Dose titration phase of up to 8 weeks
* Stable dosing period for 8 weeks

Arms: arm 1: Riociguat 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID; dose titration starting with 1.0 mg (planned up-titration every 2 weeks, with possibility of dose reduction for tolerability; 0.5 mg is the lowest dose and 2.5 mg is the highest dose to be administered) arm 2: Matching placebo tablets: 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID; dose titration starting with 1.0 mg matching placebo tablet.
Interventions: intervention 1: Riociguat intervention 2: Placebo
Intervention descriptions: intervention 1: riociguat 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID; dose titration starting with 1.0 mg (planned up-titration every 2 weeks, with possibility of dose reduction for tolerability; 0.5 mg is the lowest dose and 2.5 mg is the highest dose to be administered) intervention 2: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;

Protocol documents:
Prot_000.pdf: 
 July 10, 2017 
Investigator Study Protocol No.: Version 4 
Page 1 of 56 
 
Title page 
 
A MULTI-CENTER RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PILOT STUDY TO ASSESS THE EFFICACY AND SAFETY OF RIOCIGUAT IN 
SCLERODERMA-ASSOCIATED DIGITAL ULCERS 
Riociguat in scleroderma-associated digital ulcers 
Test drug: 
BAY63-2521/ riociguat 
Study purpose: 
Safety and efficacy of Riociguat 
Clinical study phase: 
IIa 
Version no: 
4 
Version Date 
July 10, 2017 
 
Sponsor Investigator: 
Dinesh Khanna, MD, MSc 
Professor of Medicine 
Division of Rheumatology/Dept. of Internal Medicine 
Suite 7C27 
300 North Ingalls Street Ann Arbor, MI 48109-5422 
khannad@med.umich.edu Phone: 734.232-2104 
Direct: 734.763.7182 
Fax: 734.763.5761 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether 
in part or in full - to parties not associated with the clinical investigation, or its use for any 
other purpose, without the prior written consent of the sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 


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Signature of Investigator Sponsor 
 
The signatory agrees to the content of the final clinical study protocol as presented. 
 
Signature: 
 
Name: 
Dinesh Khanna, MD, MSc 
Date: 
July 10, 2017 


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Synopsis 
 
Title 
A MULTI-CENTER RANDOMIZED, DOUBLE-BLIND, PLACEBO- 
CONTROLLED PILOT STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF RIOCIGUAT IN SCLERODERMA-ASSOCIATED DIGITAL 
ULCERS 
Short title 
Riociguat in scleroderma-associated digital ulcers 
Clinical study phase 
IIa 
Study objective(s) 
The primary objective of this study is to provide preliminary data on the 
efficacy (digital ulcer net burden) and safety of riociguat administered 3 times 
daily (TID) in comparison to placebo in patients with scleroderma-associated 
digital ulcers 
Test drug(s) 
BAY 63-2521 / riociguat 
Name of active ingredient 
BAY 63-2521 / riociguat 
Dose(s) 
0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID; dose titration 
starting with 1.0 mg (planned up-titration every 2 weeks, with possibility of 
dose reduction for tolerability; 0.5 mg is the lowest dose and 2.5 mg is the 
highest dose to be administered) 
Route of administration 
Oral 
Duration of treatment 
Total of 16 weeks, consisting of an 8-week titration period and 8 weeks of 
maintenance. 
Reference drug(s) 
Placebo 
Name of active ingredient 
Not applicable 
Dose(s) 
Matching placebo tablets to BAY 63-2521/ riociguat 0.5 mg, 1 mg, 1.5 mg, 2 
mg and 2.5 mg administered TID; dose titration starting with 1.0 mg matching 
placebo tablet. 
Route of administration 
Oral 
Duration of treatment 
Total of 16 weeks, consisting of an 8-week titration period and 8 weeks of 
maintenance. 
Background treatment 
Not applicable 
Indication 
Scleroderma-associated digital ulcers (SSc-DU) 
Site Numbers 
Up to 10 sites in the US.  Currently participating sites are listed in this 
protocol with the opportunity to add up to 5 more if necessary for recruitment 


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Diagnosis and main criteria for 
inclusion 
Men or women aged 18 years and older, inclusive 
Systemic Sclerosis as defined by 2013 the American College of 
Rheumatology (ACR) / European League Against Rheumatism (EULAR) 
classification. 
Patients had to have at least one visible, active ischemic digital ulcer(DU) or 
painful indeterminate DU at screening located at or distal to the proximal 
interphalangeal joint, and that developed or worsened within 8 weeks prior to 
screening 
Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent), nonsteroidal 
anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) 
inhibitors and calcium channel blockers are permitted if the participant is on a 
stable dose for ≥ 2 weeks before and including at baseline. 
Women of childbearing potential must have a negative urine pregnancy test at 
the screening and baseline visit, negative monthly urine pregnancy tests, and 
must use reliable methods of contraception. 
Study design 
Randomized (1:1), double-blind, placebo-controlled, parallel-group, 
multicenter, US study 
Methodology 
This study is designed to investigate the efficacy and safety of riociguat (1 
mg, 
1.5 mg, 2 mg and 2.5 mg TID; 0.5 mg is the lowest dose administered if the 
participant experiences side effects) in patients with SSc-DU. The study 
consists of two parts: 1) a main double-blind placebo-controlled 16-week 
study treatment phase, and 2) an optional 16-week open-label extension phase 
for participants with active digital ulcer/reoccurrence of digital ulcers within 1 
month of the end of the main treatment phase. 
Type of control 
Placebo 
Number of participants 
20 randomized participants 
Primary variable 
Change in digital ulcer net burden from baseline to the end of the double-blind 
study treatment phase 


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Plan for statistical analysis 
The planned sample size of 20 SSc participants is based on practical 
considerations to obtain preliminary estimates of the magnitude of treatment 
differences in efficacy and safety rather than a desired power for a pre- 
specified difference as would be necessary for a confirmatory study. 
However, with this proposed sample of 20 participants (10 riociguat and 10 
placebo), we can calculate the magnitude of treatment differences (riociguat – 
placebo) for the primary efficacy endpoint – the change from baseline to end 
of double- blind treatment in digital ulcer net burden (a continuous endpoint), 
or safety outcomes – characterized by the proportion of participants who 
experience an AE. There would be 80% power to detect an effect size (mean 
treatment difference divided by standard deviation) of 1.253 or greater with a 
two-sided type I error of 5% in the primary endpoint. Given the pilot nature of 
this Phase IIa study, the difference between mean change in digital ulcer net 
burden between riociguat and placebo that can be detected with sufficient 
power is large. Similarly, we can calculate power for safety outcomes for this 
sample size: there is 81% power to detect treatment differences of 51%, 
assuming  40% of placebo-treated participants experience an AE. 
 
Descriptive statistics will be derived for all clinical variables, mean and 
standard deviation for continuous outcomes and percentages for categorical 
and dichotomous variables. The main outcome of interest is the mean change 
in digital ulcer net burden at the end of 16 weeks in the two groups. We will 
compare the mean change in the riociguat vs. placebo groups using an 
ANCOVA model, with treatment and baseline digital ulcer net burden as 
covariates. Extension of the Wilcoxon rank-sum test to adjust for baseline 
digital ulcer net burden will be used if the assumptions of the parametric 
ANCOVA model are violated. We will also compare the proportion of 
patients with healing of the cardinal DU, the mean change in number of DUs 
from baseline to week 16, the number of new DUs during the double blind 
phase of the study, new ulcers or healing of ulcers over the distal 
interphalangeal (DIP), proximal interphalangeal (PIP), and 
metacarpophalangeal (MCP) joints and elbows, and the change in patient- 
reported outcomes (PROs) including Raynaud’s phenomenon (RP) measures 
and global assessments by the patient and physician in the riociguat vs.  
placebo group using similar methods as used for the primary endpoint for 
continuous outcomes and Fisher’s exact tests for discrete outcomes. 
 
The p-values resulting from formal statistical tests will be interpreted from a 
hypothesis-generating, rather than a confirmatory framework. 


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Table of contents 
1. Introduction ........................................................................................................................ 9 
1.1 Background ........................................................................................................................ 9 
1.1.1 
Scleroderma (systemic sclerosis) .................................................................................. 9 
1.1.2 
Riociguat ..................................................................................................................... 10 
1.1.2.1 
Mechanism of Action ............................................................................................... 10 
1.1.2.2 
Clinical Data ............................................................................................................ 10 
1.2   Rationale of the study ..................................................................................................... 11 
1.3 
Benefit-risk assessment .................................................................................................. 11 
2. Study objectives ................................................................................................................ 12 
2.1 Secondary objectives ........................................................................................................ 12 
3. Investigators ..................................................................................................................... 13 
4. Study design ...................................................................................................................... 14 
4.1 Design overview ................................................................................................................ 14 
4.1.1 
Screening phase (up to 2 weeks) ................................................................................. 15 
4.1.2 
Double-blind Treatment phase (Week 0 to Week 16)................................................. 16 
4.1.3 
Open-Label Extension phase (OLE) ........................................................................... 17 
4.1.4 
Early Termination Visit and Safety Follow-up Visit .................................................. 18 
5. Study population .............................................................................................................. 18 
5.1 Eligibility ........................................................................................................................... 18 
5.1.1 
Inclusion criteria .......................................................................................................... 18 
5.1.2 
Exclusion Criteria ........................................................................................................ 19 
5.1.3 
Justification of selection criteria ................................................................................. 20 
5.2  Withdrawal of participants from study ......................................................................... 21 
5.2.1 
Withdrawal .................................................................................................................. 21 
6. Treatment ......................................................................................................................... 22 
6.1 Treatments to be administered ....................................................................................... 22 
6.2 
Identity of study treatment .............................................................................................. 23 
6.3 
Treatment assignment ..................................................................................................... 24 
6.4 Dosage and administration ............................................................................................. 24 
6.4.1 
Selection of doses in the study .................................................................................... 24 
6.4.2 
Special populations ..................................................................................................... 24 
6.5 Blinding .............................................................................................................................. 25 
6.6 
Treatment compliance .................................................................................................... 26 
6.7 
Post-study therapy .......................................................................................................... 26 
6.8 
Prior and concomitant therapy ........................................................................................ 26 
7. Procedures and variables ................................................................................................ 27 


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7.1 Schedule of events ............................................................................................................ 27 
7.1.1 
Schedule of Events ...................................................................................................... 29 
7.1.2 
Timing of assessments ................................................................................................ 31 
7.1.2.1 
Visit 0 − Screening................................................................................................... 31 
7.1.2.2 
Visit 1 − Baseline (Day 0, Week 0) – Double-Blind Treatment Phase ................... 31 
7.1.2.3 
Visits 2 through 7 − Dose titration/Stable dosing periods (Double-blind treatment 
phase) ....................................................................................................................... 32 
7.1.2.4 
Early Termination Visit during Double Blind ......................................................... 33 
7.1.2.5 
Unscheduled visit ..................................................................................................... 33 
7.1.2.6 
Visits 8 through 14 − Dose-titration phase/ Stable dosing periods (Open label 
extension phase) ....................................................................................................... 33 
7.1.2.7 
Early Termination Visit during Open Label Extension ........................................... 34 
7.1.2.8 
Unscheduled visit ..................................................................................................... 34 
7.2  Population characteristics ............................................................................................... 34 
7.2.1 
Demographic ............................................................................................................... 34 
7.2.2. 
Medical history ............................................................................................................ 35 
7.3 
Efficacy ........................................................................................................................... 35 
7.4 
Pharmacokinetics / pharmacodynamics.......................................................................... 36 
7.5 Safety ................................................................................................................................. 36 
7.5.1 
Adverse events ............................................................................................................ 36 
7.5.1.1 
Definitions ................................................................................................................ 36 
7.5.1.2 
Classifications for adverse event assessment ........................................................... 38 
7.5.1.2.1 
Seriousness ........................................................................................................... 38 
7.5.1.2.2 
Intensity ................................................................................................................ 38 
7.5.1.2.3 
Causal relationship ............................................................................................... 38 
7.5.1.2.4 
Action taken with study treatment ........................................................................ 39 
7.5.1.2.5 
Other specific treatment(s) of adverse events ....................................................... 39 
7.5.1.2.6 
Outcome ................................................................................................................ 40 
7.5.1.3 
Assessments and documentation of adverse events ................................................. 40 
7.5.1.4 
Reporting of serious adverse events ........................................................................ 40 
7.5.1.5 
Expected adverse events .......................................................................................... 41 
7.5.1.6 
Adverse events of special safety interest ................................................................. 41 
7.5.1.7 
Overdose of Study Medication ................................................................................ 41 
7.5.2 
Pregnancies.................................................................................................................. 41 
7.6 Other procedures and variables ..................................................................................... 41 
7.6.1 
Pregnancy testing ........................................................................................................ 41 
7.6.2 
Laboratory parameters ................................................................................................ 42 
7.6.3 
Exploratory Biomarkers .............................................................................................. 42 
7.6.4 
Blood pressure and heart rate measurement ................................................................ 42 
7.6.5 
Digital ulcer net burden ............................................................................................... 42 
7.6.6 
Digital Gangrene ......................................................................................................... 43 
7.6.7 
Raynaud’s attacks assessment ..................................................................................... 43 
7.6.8 
Patient-Reported Outcomes (PROs) / Health-Related Quality of Life (HRQoL) 
questionnaires .............................................................................................................. 43 
7.6.9 
Participant and Physician Global Assessment ............................................................ 44 


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8. Statistical methods and determination of sample size .................................................. 44 
8.1 General considerations .................................................................................................... 44 
8.2 Analysis sets ...................................................................................................................... 45 
8.3 
Statistical and analytical plans ........................................................................................ 45 
8.3.1 
Demographic and other baseline characteristics ......................................................... 45 
8.3.2 
Efficacy ....................................................................................................................... 45 
8.3.3 
Safety ........................................................................................................................... 46 
8.4 
Planned interim analyses ................................................................................................ 46 
8.5 
Determination of sample size ......................................................................................... 46 
8.6 
Data recording ................................................................................................................ 47 
8.7 
Monitoring ...................................................................................................................... 47 
8.8 
Archiving ........................................................................................................................ 47 
9. Premature termination of the study ............................................................................... 48 
10. Ethical and legal aspects .................................................................................................. 49 
10.1 Ethical and legal conduct of the study ............................................................................ 49 
10.2 Compensation for health damage of participants / insurance ......................................... 49 
11. Appendices ........................................................................................................................ 49 
11.1 Child-Pugh Classification of Liver Disease ................................................................... 49 
11.2 Digital Ulcer Care Protocol ............................................................................................ 50 
12. References ......................................................................................................................... 51 


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1. 
Introduction 
 
1.1 
Background 
 
1.1.1 
Scleroderma (systemic sclerosis) 
 
Systemic sclerosis (SSc) is a rare, orphan disease featuring chronic, fibrosing, autoimmune 
responses characterized by small vessel vasculopathy, autoantibody production, and fibroblast 
dysfunction leading to increased deposition of extracellular matrix(1). 
 
Systemic sclerosis is further divided into 2 subtypes defined by the extent of skin involvement: 
limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc). In 
limited disease (formerly called CREST [calcinosis, Raynaud's phenomenon, esophageal 
dysmotility, sclerodactyly, and telangiectasias] syndrome), skin tightening is confined to the 
fingers, hands, and forearms distal to the elbows, with or without tightening of skin of the feet 
and of the legs distal to the knees. Proximal extremities and the trunk are not involved.  In 
dcSSc, the skin of the proximal extremities and trunk is also involved.  Both dcSSc and lcSSc are 
associated with internal organ involvement; however, patients with dcSSc are at greater risk for 
clinically significant major organ dysfunction. dcSSc is one of the most fatal rheumatic diseases, 
and is associated with substantial morbidity and many detrimental effects on health-related 
quality of life. 
 
SSc is an orphan disease with an estimated prevalence of 50,000 in Europe and 276 per 100,000 
in the United States (US). Applying these estimates to the 2010 US census of 309 million people, 
the project number of patients in the US with SSc is less than 100,000.  Approximately 60% 
have lcSSc and 35-40% have dcSSc. 
 
Raynaud’s phenomenon (RP) is an almost universal manifestation of SSc, with 95% of all 
patients being affected, and resulting in digital ulcers (DUs) in approximately 30% of the 
patients each year. DUs are a major clinical problem, being associated with substantial morbidity 
(reduced quality of life, pain, disability and disfigurement) that can escalate to gangrene and 
amputation in approximately 15% of patients. Treatments that have shown potential include 
calcium channel blockers, prostacyclin analogues and endothelin receptor antagonists (ERAs) . 
Bosentan, a dual endothelin receptor antagonist, is approved in Europe to reduce the number of 
new DUs in patients with SSc. However, bosentan is not approved in United States and does not 
appear to heal the ulcer. Small studies and case series have shown efficacy of PDE-5 inhibitors 
in scleroderma-spectrum DU and this finding is supported by a meta-analysis(2). 
 
Riociguat is the first-in-class of a new group of compounds, soluble guanylate cyclase (sGC) 
stimulators. Riociguat directly stimulates sGC, thereby increasing levels of the signaling 
molecule cGMP. The cGMP molecule plays a pivotal role in regulating cellular processes, such 
as vascular tone, proliferation, fibrosis, and inflammation. Two key features of riociguat are (i) it 
directly stimulates sGC independently of nitric oxide (NO), and (ii) it sensitizes sGC to low 
levels of NO.


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Riociguat has recently been approved in the US and Canada for two forms of pulmonary 
hypertension, namely pulmonary arterial hypertension (PAH) and treatment of chronic 
thromboembolic pulmonary hypertension (CTEPH). 
 
From the literature, there is ample evidence from in vitro and in vivo investigations for efficacy 
of cGMP elevation in fibrotic diseases and a large trial is planned in skin fibrosis associated with 
SSc(3-6). 
 
The goal of the current study is to provide preliminary data on the efficacy and safety of 16 
weeks of treatment with riociguat in a randomized, placebo-controlled clinical trial in patients 
with SSc-associated DU. 
 
1.1.2 
Riociguat 
 
1.1.2.1 
Mechanism of Action 
 
As described above, riociguat is the first-in-class sGC stimulator that directly stimulates sGC 
independently of NO and sensitizes sGC to low levels of NO. Because of the broad spectrum of 
cGMP actions and specific mode of action of riociguat, the efficacy of sGC stimulators for the 
treatment of patients with systemic sclerosis (SSc) was investigated.  Both, the vascular effects 
of riociguat and the direct antifibrotic effects could be beneficial for the treatment of patients 
with SSc.  More specifically, it was shown that sGC stimulators decrease collagen production in 
dermal fibroblasts from SSc patients.  In addition, sGC stimulators block fibroblast to 
myofibroblasts differentiation of dermal fibroblasts. Thus, sGC stimulators could block 
production of collagen and extracellular matrix components, which may explain, at least in part, 
the antifibrotic effects of sGC stimulators. 
 
1.1.2.2 
Clinical Data 
 
Riociguat (Adempas) was recently approved in the US and Canada for the treatment of PAH 
and/or CTEPH. 
 
The safety data described below reflect exposure to riociguat in two, randomized, double-blind, 
placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) 
and treatment naive or pre-treated PAH patients (PATENT-1). The population (Riociguat: n = 
490; Placebo: n = 214) was between the age of 18 and 80 years. 
 
The safety profile of riociguat in patients with inoperable or recurrent/persistent CTEPH 
(CHEST-1) and treatment naive or pre-treated PAH (PATENT-1) were similar. Therefore, 
adverse drug reactions (ADRs) identified from the 12- and 16-week placebo-controlled trials for 
PAH and CTEPH, respectively, were pooled, and those occurring more frequently on riociguat 
than placebo (≥3%) are displayed in Table 1 below. 
 
Most adverse reactions in Table 1 can be ascribed to the vasodilatory mechanism of action of 
riociguat. The overall rates of discontinuation due to an adverse event in the pivotal placebo- 
controlled trials were 2.9% for riociguat and 5.1% for placebo (pooled data). 


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Adverse Reactions 
Adempas 
% (n=490) 
Placebo % 
(n=214) 
Headache 
27 
18 
Dyspepsia and 
Gastritis 
21 
8 
Dizziness 
20 
13 
Nausea 
14 
11 
Diarrhea 
12 
8 
Hypotension 
10 
4 
Vomiting 
10 
7 
Anemia (including 
laboratory parameters) 
7 
2 
Gastroesophageal 
reflux disease 
5 
2 
Constipation 
5 
1 
 
Further details can be found in the Package Insert (PI), which contains comprehensive 
information on the study drug. 
 
1.2 
Rationale of the study 
 
DUs occur in approximately 30% of the patients each year (2). DUs are a major clinical problem, 
being associated with substantial morbidity (reduced quality of life, pain, disability and 
disfigurement) that can escalate to gangrene and amputation in approximately 15% of patients. 
There are no drugs approved in the US for treatment of DU. Riociguat is a direct stimulator of 
the sGC in vitro and in vivo which is independent from NO, the endogenous activator of the 
enzyme. Moreover, in the presence of NO, it enhances the effects of NO. 
 
The sGC catalyzes the production of cyclic guanosine monophosphate (cGMP) upon binding of 
NO.  Increased intracellular cGMP levels induce vasorelaxation, inhibition of cell proliferation 
and migration as well as inhibition of platelet adhesion and aggregation. 
 
Because various preclinical in vitro and in vivo data revealed that riociguat was safe and 
efficacious in PAH, the hypothesis is that riociguat may bring significant clinical benefit to 
patients with scleroderma by improving vasculopathy. In addition, riociguat has anti-fibrotic 
action that may augment the benefits in the vascular pathway. 
 
1.3 
Benefit-risk assessment 
 
There are currently no disease-specific pharmacotherapies approved for healing of DU and 
therefore there is a high unmet medical need in this indication. During the pivotal riociguat 
PATENT-1 trial for PAH, participants with PAH-SSc were included and the overall benefit-risk 
profile was positive. 
 
Considering the mechanism of action of riociguat and the results of the PAH trials, we believe 
that riociguat will: 


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 Decrease digital ulcer net burden. 
 Heal digital ulcers. 
 Decrease number and severity of Raynaud’s attacks. 
 
Taking into account the seriousness of the disease as well as the medical need for an effective 
and safe therapy, on balance the expected benefit to participants with this life-threatening 
condition outweighs potential risks. 
 
2. 
Study objectives 
 
The primary objective of this study is to provide preliminary data on the efficacy (digital ulcer 
net burden) of riociguat administered 3 times daily (TID) in comparison to placebo in patients 
with SSc. 
 
The primary efficacy outcome is the change from baseline to end of double-blind treatment in 
digital ulcer net burden.  Digital ulcer net burden is defined as the total number of “active” and 
indeterminate digital ulcers at an assessment. 
 
 
 
2.1 
Secondary objectives 
 
The secondary objectives of this study are to provide preliminary data on safety and additional 
measures of efficacy of riociguat administered TID as compared with placebo. 
 
Additional efficacy measures include: 
 
 Healing of the cardinal DU. For each participant, one digital ulcer must be identified 
and designated by the investigator as the cardinal ulcer at screening. The cardinal ulcer 
must have met the qualifications for designation as an active or painful indeterminate 
ulcer. If only one ulcer was determined at entry to be active or painful indeterminate, it 
will be designated as the cardinal ulcer. If several digital ulcers qualified, the cardinal 
ulcer could be either the largest or the most painful ulcer, or the ulcer that disturbed the 
patient the most. The cardinal ulcer will be selected by the investigator based on the 
clinical judgment that it was amenable to and evaluable for healing. 
 Development of DU 
 Development and healing of pressure ulcers over the Distal Interphalangeal 
(DIP), Proximal Interphalangeal (PIP), Metacarpophalangeal (MCPs) and 
elbows. 
 Time to healing of cardinal DU 
 Time to healing of all DU 
 Improvement of Raynaud’s phenomenon (RP) (7, 8) 
o Raynaud’s condition score 
o Number of Raynaud’s attacks/day 
o Patient and physician assessment of RP; pain, numbness, and tingling during an 


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RP attack; and duration of attacks 
 Patient’s and physician’s global assessment on a Likert scale 
 Health-related quality of life (HRQOL) using PROMIS-29 
 Physical function as assessed by HAQ-DI and HDISS-DU 
 Visual analog scales from scleroderma-health assessment questionnaire (SHAQ) 
assessing burden of digital ulcers, Raynaud’s disease, gastrointestinal involvement, 
breathing, and overall disease 
 Digital ischemia requiring intravenous prostacyclin or digital gangrene or amputation 
 Vascular biomarkers in the plasma (VEGF, tPA, sE-Selectin, BFGF, VCAM-1, ICAM) 
 
Safety  outcomes  include  adverse  events,  clinically  significant  changes  in  vital  signs, 
laboratory test abnormalities, and clinical tolerability of the drug. 
 
3. 
Investigators 
 
Title/Name: 
MD, Address: 
 
 
Telephone No: 
Fax No: 
Site Investigator, Dinesh Khanna, MD, MSc, University of Michigan 
300 North Ingalls Street, NI7C27 
Ann Arbor, MI 48109-5422 
USA 
+1(734) 763-7182 
+1(734) 763-5761 
 
 
Title/Name: 
MD, Address: 
 
 
 
 
Telephone No: 
Site Investigator, Virginia Steen 
Georgetown University Hospital 
Department of Rheumatology, Immunology, & Allergy 
3800 Reservoir Road, NW 
3PHC, Suite 3004E 
Washington, DC  20007 
+1(202) 444-6200 
 
 
Title/Name: 
MD, Address: 
 
 
 
Telephone No: 
Site Investigator, Robyn T. Domsic, MD, MPH 
University of Pittsburgh School of Medicine 
S726 Biomedical Science Tower 
3500 Terrace Street 
Pittsburgh, PA 15261 
+1 (412) 648-7040 
 
 
Title/Name: 
MD, Address: 
 
 
Telephone No: 
Site Investigator, Tracy Frech, MD 
University of Utah, Division of Rheumatology 
30 North 1900 East 4B200 SOM 
Salt Lake City, UT 84132 
+1(801) 581-4333 
 
 
Title/Name: 
MD, Address: 
 
Site Investigator, Jessica Gordon, MD 
Hospital of Special Surgery, Division of Rheumatology 
535 East 70th Street 


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Telephone No: 
New York, NY 10035 
+1(212) 774-7381 
 
Data Safety and Monitoring Board 
 
An independent data and safety monitoring board (DSMB) will be convened that will review 
safety data. The purpose of the DSMB is to assure independent review as to whether study 
participants are exposed to unreasonable risk because of study participation.  Detailed 
information on the roles and responsibilities of the DSMB will be described in the DSMB 
Charter. 
 
4. 
Study design 
 
4.1 
Design overview 
 
This clinical trial is a US, multicenter, double-blind, randomized placebo-controlled, parallel- 
group study with a total of 20 participants planned to be randomized (approximately 10 
participants to the riociguat group and 10 to the placebo group). In addition, a standardized 
wound care protocol (see Appendix 11.2) will be followed by the investigators and digital 
photography will be taken of the cardinal ulcer. 
 
The study will allow standard of care medications for the management of DU as background 
therapy. These may include calcium channel blockers, low dose aspirin, angiotensin enzyme 
inhibitors, etc. and will be determined by the participant’s local physician. 
 
The study design consists of three phases: 
 
 Screening phase: up to 2 weeks 
 
 Double-blind Treatment phase: 16 weeks of double-blind treatment, consisting of: 
o Dose titration period of up to 8 weeks, and 
o Stable dosing period of up to 8 weeks 
 
 Open-label Extension phase for participants with active or painful indeterminate DU at 
the end of the double- blind treatment phase or development of an active or painful 
indeterminate DU within a month of completing double-blind phase, consisting of: 
o Dose titration phase of up to 8 weeks 
o Stable dosing period for 8 weeks 
 
 


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4.1.1 
Screening phase (up to 2 weeks) 
 
After providing written informed consent, participants will undergo a screening evaluation to 
determine their eligibility (see Section 7.1 for a detailed schedule of events).  Participants will 
complete a diary detailing the number and duration of Raynaud’s attacks per day for a period of 
at least 7 consecutive days leading up to the start of treatment / Day 0. 
If the Raynaud’s attack diary can be completed prior to the screening visit it will allow the 
patient with a painful ulcer to be screened and randomized the same day thereby eliminating the 
burden of an additional clinic visit.   
 
4.1.2 
Double-blind Treatment phase (Week 0 to Week 16) 
 
At the baseline visit, participants who have met all of the inclusion and none of the exclusion 
criteria will be randomized in 1:1 fashion to riociguat or placebo using a web-based 
randomization system. 
 
Dose titration phase (Visits 1 to 5) 
 
In the first 8 weeks of the double-blind treatment phase, participants will undergo individual 
dose titration. 
 
The starting dosage is 1.0 mg TID.  The dose should be increased by 0.5 mg increments no 
sooner than 2 weeks(± 4 days) apart to 1.5 mg, 2 mg and 2.5 mg TID, resulting in a maximum 
total daily dose of 7.5 mg (2.5 mg TID).  Participants can be maintained on a lower dose if 
higher doses are not tolerated (minimum dosage of 0.5 mg TID, total daily dose 1.5 mg).  It is 
possible for a participant to be up-titrated and then down-titrated during the course of this phase 
of the study. 


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However, once a participant has been down-titrated, they will remain at that dose and escalation 
will not be implemented again.  If necessary, a participant can down-titrate multiple times to a 
minimum of 0.5 mg TID. 
 
To maintain blinding of the treatment arms, participants randomized to the placebo group will 
undergo sham titration from Visit 1 onwards during the dose-titration period following the rules 
of the individual dose titration scheme. 
 
Individual dose titration algorithm 
 
The individual study medication dose for the next titration step will be determined every 2 weeks 
according to the patient’s well-being and the peripheral systolic blood pressure (SBP) measured 
at trough before intake of the morning dose according to the following algorithm (individual 
dose titration scheme): 
 
 If SBP is ≥ 95 mmHg and the participant has no signs or symptoms of hypotension, the 
dosage should be increased by 0.5 mg TID. If the participant has signs or symptoms of 
hypotension, the dose should be decreased by 0.5 mg TID, regardless of SBP. 
 If SBP is < 95 mmHg, the dosage should be maintained provided the participant does not 
show any signs or symptoms of hypotension. 
 If SBP is < 95 mmHg and the participant exhibits signs or symptoms of hypotension the 
current dosage should be decreased by 0.5 mg TID.  
 If the participant develops SBP < 95 mmHg or exhibits signs or symptoms of 
hypotension on 0.5 mg TID, then the participant is discontinued from study medication 
but should continue with follow-up visits. The participant may continue in the open label 
phase at the discretion of the PI if an active or painful indeterminate DU is present at 
week 16 or week 20.   
 
Stable dosing period (Visits  6, and 7) 
 
The overall duration of the double-blind treatment phase is 16 weeks, including the dose titration 
period.  At the end of the dose titration period (Week 8/Visit 5), the participant’s stable dose for 
the next 8 weeks will be determined using the treatment algorithm above.  No further increase in 
dose will be allowed.  The established individual dose will then be taken as the “optimal 
individual dose” to be administered for the remaining duration of the main study (up to Week 
16). 
 
Dose reductions for safety reasons (e.g., in case of any treatment-emergent adverse event [AE]) 
are allowed, but a subsequent dose increase during the maintenance period is not permitted. 
 
Dose Interruptions 
 
If treatment is interrupted between visits for any reason other than signs and symptoms of 
hypotension, the following rules should be applied: 
 


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 ≤ 3 consecutive days without treatment:  restart with last dose 
 > 3 days but ≤ 14 consecutive days without treatment it is at the discretion of the 
investigator whether the study medication can be restarted: if  restarted, start with last 
dose 
 > 14 consecutive days without treatment:  withdraw the participant from study 
medication (but continue follow-up in the study). 
 
The algorithm below will be followed for dose titration at study visits 2-5 and OL Visits 9-12 if 
treatment is interrupted for any length of time: 
 
# of missed days 
(consecutive) 
No Signs or 
symptoms of 
hypotension 
and SBP ≥ 95 mmHg 
Signs or symptoms 
of hypotension 
present 
(any SBP) 
No signs or symptoms of 
hypotension but SBP < 95 
mmHg 
0 
Up titrate 
Down Titrate 
Same Dose 
≤ 3  and missed 
days do not 
include day prior 
to visit 
Up titrate 
Down Titrate 
Same Dose 
≤ 3 and missed 
days include day 
prior to visit 
Same Dose 
Down Titrate 
Same Dose 
4-14 
Same Dose 
Down Titrate 
Same Dose 
> 14 
Stop Study Med 
Stop Study med 
Stop Study med 
 
4.1.3 
Open-Label Extension phase (OLE) 
 
At Visit 7 (Week 16), all participants with active or painful indeterminate DU will be offered the 
opportunity to initiate active treatment with riociguat, as part of the open-label phase. 
 
At Visit 7 (Week 16), participants without an active or painful indeterminate DU will stop 
double-blind therapy and be scheduled for a Safety Follow-up at Week 20. Those who have a 
reoccurrence of DU prior to and including their scheduled Week 20 visit (i.e., the 4 week period 
after the end of the double- blind period), will be offered open-label riociguat.  Those who do not 
develop an active DU by Week 20 will terminate the study at the Week 20 visit. 
 
 
 All participants who agree to remain in the study for the OLE, regardless of their original 
randomized treatment, will receive riociguat for an additional 16 weeks according to the 
dose-titration and stable dosing regimen that was used in the double blind phase, starting 
with 1.0 mg riociguat.   
 
Figure 7.1 provides a flow diagram of the end of double-blind to either end-of-study or start of 
open-label extension phases of the study. 
 
Dose Titration Phase (Visits 7 to 12) 


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At Visit 7 (Week 16), all participants who agree to continue in the open-label extension will be 
assigned to treatment with riociguat. During the first 8 weeks of the open-label extension phase, 
participants previously on placebo will be up-titrated on riociguat according to the individual 
titration algorithm described above in the double-blind treatment phase. Participants randomized 
to riociguat in the double-blind study treatment phase will also undergo titration (to protect the 
blind of the double-blind portion of the study). 
 
Stable dosing period (Visits 13 and 14) 
 
Stable dosing will continue for another 8 weeks. 
 
4.1.4 
Early Termination Visit and Safety Follow-up Visit 
 
A termination visit and a safety follow-up visit (4 weeks after last dose of study medication) 
should be performed for all patients who withdraw from study at any time during the double 
blind phase.  A termination visit should be performed for anyone who withdrawals early during 
the OLE.  If there are no study medication related Adverse events nor any digitial ulcers the 
follow-up visit can be performed as a phone call to alleviate the participant’s burden  of an in 
person clinic visit. 
 
5. 
Study population 
 
5.1 
Eligibility 
 
5.1.1 
Inclusion criteria 
 
Participants must meet the following criteria to be eligible for enrollment in the study: 
 
1. Signed written informed consent 
2. Men or women aged 18 years and older 
3. Diagnosis of Systemic sclerosis, as defined by 2013 American College of Rheumatology/ 
European Union League Against Rheumatism classification of SSc 
4. Patients had to have at least one visible, active ischemic DU or painful indeterminate DU   at 
screening located at or distal to the proximal interphalangeal joint, and that developed or 
worsened within 8 weeks prior to screening.   
Figure 5.1 
 


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5. Females of reproductive potential (FRP) must have a negative, pre-treatment urine 
pregnancy test. 
6. FRP must obtain monthly urine pregnancy tests during treatment and one month after 
treatment discontinuation.  Post-menopausal women (defined as no menses for at least 1 
year or post-surgical from bilateral oophorectomy) are not required to undergo a 
pregnancy test. 
7.   FRP and all non-vasectomized male participants must agree to use reliable contraception 
when sexually active. (For FRP’s,  ‘Adequate contraception’ is defined as any 
combination of at least 2 effective methods of birth control, of which at least one is a 
physical barrier (e.g., condoms with hormonal contraception or implants or combined 
oral contraceptives, certain intrauterine devices). This applies from the time of signing 
the informed consent form until one month after the last study drug administration.) 
8. Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent), nonsteroidal anti- 
inflammatory drugs (NSAIDs), angiotentin receptor blockers, angiotensin converting 
enzyme (ACE) inhibitors and calcium channel blockers are permitted if the participant is 
on a stable dose for ≥ 2 weeks prior to and including the baseline visit 
9. Ability to comply with the clinical visits schedule and the study-related procedures. 
 
5.1.2 
Exclusion Criteria 
 
Participants who meet any of the following criteria will be excluded from enrollment in the 
study: 
 
1. Active DU related to calcinosis (as assessed by clinical examination or radiographic 
evaluation at screening) 
2. Medical and surgical history 
 Major surgery (including joint surgery) within 8 weeks prior to screening 
 Participants with a history of malignancy in the last 5 years other than non-
melanoma skin cell cancers cured by local resection or carcinoma in situ 
3. Hepatic-related criteria 
 Hepatic insufficiency classified as Child-Pugh C at screening (see Appendix 11.1 


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for classification table) at screening visit 
4. Renal-related criteria 
 Estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73m2 (MDRD 
formula) or on dialysis at the screening visit 
5. Cardiovascular-related criteria 
 Sitting systolic blood pressure < 95 mmHg at the screening visit 
 Sitting heart rate < 50 beats per minute (BPM) at the screening visit 
 Left ventricular ejection fraction < 40% prior to screening on echocardiogram 
done as part of clinical care 
6. Pulmonary-related criteria 
 Active state of hemoptysis or pulmonary hemorrhage, including those events 
managed by bronchial artery embolization 
 Any history of bronchial artery embolization or massive hemoptysis within 3 
months prior to screening. Massive hemoptysis being defined as acute bleeding 
>240 mL in a 24-hour period or recurrent bleeding >100 mL/d over several days 
 PAH requiring pharmacologic therapy. 
 Significant pulmonary disease with FVC ≤ 50% of predicted, or DLCO 
(uncorrected for hemoglobin ) ≤ 40% of predicted 
7. Laboratory examinations 
 Participants with hemoglobin < 9.0 g/dL, white blood cell (WBC) count < 
3000/mm3 (< 3 × 109/L), platelet count < 100,000/mm3 (< 3 × 109/L) at the 
screening visit 
8. Prior and concomitant therapy 
 Concomitant use of nitrates or NO donors (such as amyl nitrate) in any form, 
including topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as 
sildenafil, tadalafil, vardenafil); and nonspecific PDE5 inhibitors (theophylline, 
dipyridamole).  If the patient is on PDE5 inhibitors, a wash out of 3 days is 
required for sildenafil and 7 days for tadalafil or vardenafil prior to the 
baseline visit 
 Concomitant Endothelin receptor antagonist 
 Patients who are actively smoking at time of consent. (Quit date of two weeks 
prior to screening acceptable) 
9. Pregnant or breastfeeding women 
10. Other 
 Any other condition or therapy that would make the participant unsuitable for this 
study and will not allow participation for the full planned study period 
 Participation in another clinical study with an investigational drug or medical 
device within 30 days prior to randomization (phase I-III clinical studies) 
 
Note: One re-assessment of laboratory parameters is allowed during the screening phase to 
assess the eligibility of participants. 
 
5.1.3 
Justification of selection criteria 
 
The selection criteria were carefully selected to exclude participants from the study who may 


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potentially be exposed to specific risks after administering the study drug as well as participants 
with conditions that may have an impact on the aims of this study. 
 
5.2 
Withdrawal of participants from study 
 
5.2.1 
Withdrawal 
 
Participants must be withdrawn from the study for the following reasons: 
 
 At their own request or at the request of their legally acceptable representative 
At any time during the study and without giving reasons, a participant may decline to 
participate further.  The participant will not suffer any disadvantage as a result. 
 If, in the investigator's opinion, continuation of the study would be harmful to the 
participant's well-being 
 Occurrence of AEs or intercurrent diseases which the investigator judges unacceptable 
for continuation of participation in the study 
 Occurrence of adverse drug reactions, which in the investigator’s opinion have a negative 
impact on the participant’s individual risk-benefit ratio.  (Investigators are obliged to 
reassess the participant’s individual risk-benefit ratio on a continuous basis. Factors such 
as anticipated treatment effect, progression of underlying disease, occurrence of side 
effects, and alternative treatment options must be considered.) 
 Non-compliance with the conditions for the trial or instructions by the investigator that 
could negatively affect the participant or impact the validity of the clinical trial. 
 Although not preferred, participants may interrupt their intake of study medication for 
reasonable circumstances/reasons at any time (e.g., hospitalization in a remote hospital 
without study medication access, safety reasons, and side effects).  If an interruption lasts 
longer than 14 consecutive days, the participant must be withdrawn from treatment, but 
continue with follow-up visits. The participant will have the opportunity to participate in 
OLE if s/he meets the criteria.  In case treatment requires interruption for > 3 days and ≤ 
14 days, it is at the discretion of the investigator if the study medication can be restarted. 
 In case of pregnancy or breast feeding. 
 In case a female patient of childbearing potential is not compliant with 4-weekly 
pregnancy testing. 
 Participation in another clinical trial.  Participation in observational registries is allowed. 
 In case no further dose reduction is possible and the participant does not tolerate the 
lowest possible riociguat dose (0.5 mg TID). 
 
Participants may be withdrawn from the study for the following reasons: 
 
 At the specific request of the sponsor and in liaison with the investigator (e.g., safety 
concerns). 
 Development of DU complications requiring prostacyclin therapy, gangrene, or 
amputation. 
 
Escape therapy 
 


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There is no escape therapy.  If a participant decides to stop study medication due to AEs or lack 
of efficacy, they will be encouraged to stay in the study and will be treated by the physician 
using standard of care. 
 
All reasons for withdrawal (including lost to follow up), will be recorded in the eCRF and site 
medical record. 
 
In the event that a participant is lost to follow-up, every possible effort must be made by study 
site personnel to contact the participant to obtain complete data and determine the reason for 
withdrawal. 
 
A participant may withdraw from further participation in the study and still allow further release 
of information. In this situation, the participant’s consent to the collection of further data should 
be documented in the site’s source documents. 
 
 
6. 
Treatment 
 
6.1 
Treatments to be administered 
 
Test Drug: 
Riociguat/ placebo 
Dosage: 
0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg (individual dose titration) 
Route of administration: 
Oral 
Time and frequency of 
administration: 
 
TID 
 
The individual optimal dose should be determined during the initial 8-week dose titration period 
based on monitoring of the participant’s systolic blood pressure and well-being. 
 
The starting dose is 1.0 mg TID. The intervals between drug intake should be 6-8 hours.  The 
dosage should be increased by 0.5 mg increments no sooner than 2 weeks apart to 1.5 mg, 2 mg, 
and 2.5 mg TID, resulting in a maximum total daily dose of 7.5 mg (2.5 mg TID).  Participants 
should be maintained on lower doses if higher doses are not tolerated (minimum dose of 0.5 mg 
TID.).  If the participant cannot tolerate 0.5 mg po TID, then the participant is discontinued (see 
section  5.2.1). After the dose titration period, riociguat should be continued at the optimal 
individual dose for the duration of the stable dosing period. 
 
6.2 
Identity of study treatment 
 
Riociguat 
 
Riociguat is supplied in various strengths as film-coated, immediate-release tablets. (see Table 0-
1) 


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All study drugs will be labeled according to the requirements of local law and legislation. Label 
text will be approved according to the sponsor’s agreed procedures, and a copy of the labels will 
be made available to the study site upon request. 
 
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be traced 
back to the respective bulk ware of the ingredients.  Lists linking all numbering levels will be 
maintained by the sponsor’s clinical supplies Quality Assurance group. 
 
A complete record of batch numbers and expiry dates of all study treatment, as well as the labels, 
will be maintained in the sponsor study file. Almac will act as central distributor for the drug and 
coordinate drug distribution with the clinical sites. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 0-1 
Identity of investigational product 
International non-
proprietary name (INN) 
Riociguat 
Sponsor’s internal 
reference number 
BAY 63-2521 
Formulation 
Film-coated tablets 
Galenical form 
Round immediate-release tablets, diameter 6 mm 


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Composition 
Active ingredient: 
Methyl 4,6-diamino-2-[1-(2- fluorobenzyl)-
1H-pyrazolo [3,4 b]pyridine-3-yl]-5- 
pyrimidinyl (methyl)carbamate 
 
Empirical formula: C20H19FN8O2  
 
Molar mass: 
422.42 g/mol (molarity) 
 
Excipients: 
lactose, microcrystalline cellulose, 
magnesium stearate, crospovidone* , 
hypromellose*, and sodium lauryl 
sulphate* 
 
Coating: 
hydroxypropyl cellulose, hypromellose, 
propylene glycol, iron oxide (red and 
yellow), and titanium dioxide. 
Strength 
0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg 
Material numbers 
83296470 BAY 63-2521 TABL 0.5 mg 511 COAT 
83296535 BAY 63-2521 TABL 1 mg 512 COAT 
83296543 BAY 63-2521 TABL 1.5 mg 513 COAT 
83296578 BAY 63-2521 TABL 2 mg 504 COAT 
83296608 BAY 63-2521 TABL 2.5 mg 515 COAT 
Packaging 
High-density polyethylene (HDPE) bottles 
Abbreviation: TABL = tablet 
*Not in placebo tablets 


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Matching placebo 
 
Matching placebo tablets will appear identical to active riociguat tablets but will not contain 
active study drug product (riociguat) or any of the asterisked excipients as outlined in Table 0-1. 
 
Riociguat and placebo tablets will have similar appearance at all dose strengths.  They will be 
labeled “BAY 63-2521/placebo” and a med number that will be assigned by IVRS. 
 
All study drugs will be labelled according to the requirements of local law and legislation. 
 
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request. 
 
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk ware of the ingredients. Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies Quality Assurance group. 
 
A complete record of batch numbers and expiry dates of all study treatment, as well as the 
labels, will be maintained in the sponsor study file. 
 
Storage requirements: 
 
All investigational drugs used during the trial will be stored at the investigational sites at room 
temperature in a place inaccessible to unauthorized personnel, i.e. in a locked cabinet. 
No special storage conditions are required. 
 
6.3 
Treatment assignment 
 
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. 
Participants who complete all screening procedures and meet all the eligibility criteria are to be 
randomized in a 1:1 ratio to receive either riociguat or placebo. The randomization schedule will 
be prepared by the Data Coordinating Center (DCC) using a computer-generated block 
randomization with the block size(s) known only by the DCC statistician  
 
6.4 
Dosage and administration 
 
6.4.1 
Selection of doses in the study 
 
Riociguat has been safe and well tolerated in previous clinical studies at multiple doses between 
0.5 and 2.5 mg TID in patients with various forms of PH, including PAH, CTEPH, and, in a 
small patient population, SSc-related PH. The starting dose for this study will be at 1.0 mg PO 
TID. 
 
6.4.2 
Special populations 
 


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Riociguat has not been studied in all populations. Particular care should be exercised when 
dosing the following: 
 
Elderly 
 
In elderly patients (≥65 years) particular care should be exercised during individual dose titration 
as this population showed a higher exposure. 
 
Renal impairment 
 
Patients with mild, moderate or severe renal impairment (creatinine clearance 15-80 mL/min) 
showed a higher exposure to riociguat. Patients with creatinine clearance <15 mL/min or on 
dialysis have not been studied. Therefore, the use of riociguat is not recommended in these 
patients who are consequently excluded from the study. 
 
Hepatic impairment 
 
Patients with moderate hepatic impairment (Child- Pugh B) showed a higher exposure to 
riociguat. Patients with severe hepatic impairment (Child-Pugh C) have not been studied 
(Appendix 11.1). Therefore, the use of riociguat is not recommended in these patients who are 
consequently excluded from the study. 
 
Smokers 
 
Plasma concentrations in smokers are reduced by 50-60% compared to nonsmokers. Safety and 
effectiveness of riociguat doses higher than 2.5 mg three times a day have not been established. 
Smokers should not be enrolled in this study. Participants who have quit at least two weeks prior 
to screening may be considered as a “non-smoker. 
 
6.5 
Blinding 
 
The study will be conducted in double-blind fashion.  Active riociguat and placebo tablet 
formulations will be identical in appearance (size, shape, color) and smell.  The packaging and 
labeling will be designed to maintain blinded conditions for the investigator’s team and the 
participants. The study data will remain blinded until database lock and authorization of data 
release according to standard operating procedures. 
 
Unblinding by drug safety personnel of the sponsor 
 
For regulatory reporting purposes, drug safety personnel of the sponsor are permitted to unblind 
individual cases. 
 
In compliance with applicable regulations, in the event of a suspected unexpected serious 
adverse reaction (SUSAR) (see Section 7.5.1.4), the participant’s treatment code will usually be 
unblinded before reporting to the health authorities, Independent Ethics Committees / 
Institutional Review Boards (IRBs), and investigators (see Section 7.5.1.4) if the SUSAR was 


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related to the blinded treatment. 
 
Emergency unblinding by the investigator 
 
In case of emergency, investigators are permitted to unblind individual cases. However, 
investigators are obligated to restrict such unblinding to cases of emergency where the 
unblinding result is of importance for the acute treatment strategy. 
 
Investigators should note that the occurrence of an SAE should not routinely precipitate the 
immediate unblinding of the label.  If unblinding is necessary for the treatment of a participant 
with an SAE, every attempt should be made to contact the investigator sponsor prior to 
unblinding. 
 
If a participant misses a menstrual period or suspects that they are pregnant, they should  stop 
study medication immediately and should be unblinded to determine if they have received 
riociguat if the pregnancy is confirmed . 
 
Drug logistics and accountability 
 
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the sponsor, and will be inaccessible to unauthorized personnel.  Special storage 
conditions and a complete record of batch numbers and expiry dates can be found in the sponsor 
study file; the site-relevant elements of this information will be available in the investigator site 
file. The responsible site personnel will confirm receipt of study drug and will use the study drug 
only within the framework of this clinical study and in accordance with this protocol. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the sponsor’s agreed and specified procedures. 
 
Written instructions on medication destruction will be made available to affected parties as 
applicable. 
 
6.6 
Treatment compliance 
 
A drug dispensing log will be completed for each participant. The date of dispensing the study 
drug to the participant will be documented. 
 
Participants will receive study medication dispensed per visit schedule (see Section 7.1). 
 
To record treatment compliance, participants will be instructed to bring all study drug packaging, 
including unused study drug and empty packaging, to the investigative site at each study visit. 
Tablets will be counted for a compliance check. 
 
If a dose of study drug is missed, the participant should take a dose immediately and continue 
with the TID intake as recommended on the following day. The dose should not be doubled to 
make up for a missed dose within the same day. 


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Participants should not take study drug the day of their clinic visit at the end of the double-blind 
period of the study (Visit 7/Week16). 
 
6.7 
Post-study therapy 
 
In case participants permanently discontinue study drug treatment during this study, further 
therapy is at the discretion of the investigator. 
 
6.8 
Prior and concomitant therapy 
 
A summary of the prohibited prior and concomitant therapy, outlined in the exclusion criteria 
(Section 5.1.2), is provided in Table 6-1. 
 
Table 6-1 
Prohibited prior and concomitant therapy 
Therapy 
Timeframe 
Nitrates or NO donors (such as amyl nitrate) in any form, 
including topical; phosphodiesterase (PDE) 5 (PDE5) 
inhibitors (such as sildenafil, tadalafil, vardenafil); and 
nonspecific PDE inhibitors (theophylline, dipyridamole) 
Concomitant therapy 
with study drug 
 
In addition, caution is advised during the intake of any of the following concomitant 
medications: 
 
 The concomitant use of riociguat with strong multi-pathway cytochrome P450 (CYP) and 
P-glycoprotein 1 (P-gp)/breast cancer resistance protein inhibitors such as azole 
antimycotics (e.g., ketoconazole, itraconazole) or human immunodeficiency virus 
protease inhibitors (e.g., ritonavir) is not recommended, due to the pronounced increase 
in riociguat exposure. 
 The concomitant use of riociguat with strong CYP1A1 (CYP family 1, subfamily A, 
polypeptide 1) inhibitors, such as the tyrosine kinase inhibitor erlotinib, and strong P-gp 
inhibitors, such as the immunosuppressive agent cyclosporine A, may increase riociguat 
exposure (see section ‘interaction with other medicinal products and other forms of 
interaction’). These drugs should be used with caution.  Blood pressure should be 
monitored and dose reduction of riociguat considered. 
 
Other medications considerations 
 
 Pre- and concomitant treatment with the proton pump inhibitor omeprazole (40 mg once 
daily) reduced riociguat mean area under the plasma concentration versus time curve 
(AUC) by 26% and mean maximum plasma concentration (Cmax) by 35%.  This is not 


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considered clinically relevant. 
 Co-administration of the antacid aluminum hydroxide / magnesium hydroxide reduced 
riociguat mean AUC by 34% and mean Cmax by 56%. Antacids should be taken at least 
1 hour after riociguat. 
 
7. 
Procedures and variables 
 
7.1 
Schedule of events 
 
The study will be divided into the following phases:  screening phase, double-blind treatment 
phase, and open-label extension phase.  Please refer to Section 7.1.1 for the schedule of events. 
 
Figure 7.1 Flow diagram of Double Blind to Open Label Transition 
 
 
 


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7.1.1 
Schedule of Events 
 
Study Period: Double-Blind 
Phase 
Dose Titration Period 
Stable Dosing Period 
Safety h 
Follow Up 
Study Visit 
Screening 
Visit 0 
Baseline 
Visit 1 
Week 2 
Visit 2 
Week 4 
Visit 3 
Week 6 
Visit 4 
Week 8 
Visit 5 
UNSHf 
Week 12 
Visit 6 
Week 
16g 
Visit 7
Week 20 
Visit 8 
Window (days): 
14 
+4 
+/-4 
+/-4 
+/-4 
+/-4 
 
+/-4 
+/-4 
+/-4 
Type of Contact: 
Office 
Office 
Office 
Office 
Office 
Office 
Office 
Office 
Office 
Office/Phone 
Call 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
 
 
Demographics, including smoking & 
alcohol history 
X 
 
 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
Prior/Concomitant therapy 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
X 
 
 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
 
X 
 
Hematology, serum chemistrya 
X 
 
 
 
 
X 
 
 
X 
 
Urine pregnancy test (women of 
childbearing potential) 
X 
X 
 
X 
 
X 
 
X 
X 
 
Hand x-rays for calcinosis (not 
required at Screening if performed in prior 
6  months) 
X 
 
 
 
 
 
 
 
 
 
Physician’s Global Assessment 
 
X 
 
 
 
 
 
 
X 
 
Patient’s Global Assessment 
 
X 
 
 
 
 
 
 
X 
 
PROMIS -29 
 
X 
 
 
 
 
 
 
X 
 
HAQ-DI/SHAQ 
 
X 
 
 
 
 
 
 
X 
 
HDISS-DU 
 
X 
 
 
 
 
 
 
X 
 
Raynaud’s phenomenon diary 
Xb 
Xc 
 
 
 
 
 
Xb 
Xc 
 
Digital Ulcer Assessment 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Digital photo of cardinal ulcer 
X 
 
 
 
 
 
 
 
X 
 
Dispense study medication 
 
X 
X 
X 
X 
X 
X 
X 
Xd 
 
Assess for Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Biomarkerse 
 
X 
 
 
 
 
 
 
X 
 


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a Participants with eGFR 15-29 ml/min or other laboratory abnormalities per physician judgment can repeat labs once during the screening period 
b Dispense 7-day diary; 
c Collect 7-day diary; 
d Open-Label study drug will be dispensed at this visit if participant is continuing to the OLE phase of the study. If a participant is exiting the study, all study drug should be 
returned at this visit and no more will be dispensed. 
e 10 mL for biomarkers: VEGF, tPA, sE-Selectin, BFGF, VCAM-1, ICAM 
f  This visit is for participants who experience toleration issues and return to clinic for assessment and dispense a lower dose. 
g Complete these visit assessment for any participants who terminate/withdrawal from the study prior to visit 7. 
h Complete this visit for any subject who does not enter the OLE. This can be a phone call if there are no new or ongoing adverse events attributable to the study medication  
and no digital ulcers to assess.  
 


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Study Period: Open-
Label Phase 
Dose Titration Period 
Stable Dosing 
Period 
Study Visit 
OLE 
Week 0a 
Visit 8 
OLE 
Week 2 
Visit 9 
OLE 
Week 4 
Visit 10 
OLE 
Week 6 
Visit 11 
OLE 
Week 8 
Visit 12 
OLE 
Week 12 
Visit 13 
OLE 
Week 
16/EOSc 
Visit 14 
UNSHd 
Window: 
+4 
+/-4 
+/-4 
+/-4 
+/-4 
+/-4 
+/-4 
 
Type of Contact: 
Office 
Office 
Office 
Office 
Office 
Office 
Office 
Office 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X
b 
 
 
 
 
 
X 
X 
12-lead ECG 
X
b 
X 
 
 
 
 
X 
 
Hematology, serum chemistry 
Xb 
 
 
 
X 
 
X 
 
Urine pregnancy test (women of 
childbearing potential) 
X 
 
X 
 
X 
X 
X 
 
Physician’s Global Assessment 
X 
 
 
 
 
 
X 
 
Patient’s Global Assessment 
X 
 
 
 
 
 
X 
 
PROMIS -29 
X 
 
 
 
 
 
X 
 
HAQ-DI/SHAQ 
X 
 
 
 
 
 
X 
 
HDISS-DU 
X 
 
 
 
 
 
X 
 
Digital Ulcer Assessment 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study medication 
X 
X 
X 
X 
X 
X 
 
X 
Assess for Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
a Visit 8 would be performed for a participant who completed the double blind week 16 without DU and then returned to the clinic within the protocol 
timeline parameters with a new DU and wants to continue onto the OLE phase. For those participants who had active DU(s) at end of double blind and 
proceeded into the OLE immediately Visit 7/Visit 8 run concurrently (Visit 7→ Visit 9) 
b The safety labs, ECG and physical exam do not need to be repeated at visit 8 if the participant returns with a DU within 7 days of completing the Visit 7. 
c Complete this visit as an Early Termination/End of Study visit for any participant who ends the study prior to OLE Week 16/Visit 14. 
d his visit is for participants who experience toleration issues and return to clinic for assessment and dispense a lower dose. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.2 
Timing of assessments 


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If not stated otherwise, all assessments and procedures will be performed by or under the 
supervision of an investigator. 
For timing of assessments and procedures, please refer to Section 7. 
 
7.1.2.1 
Visit 0 – Screening 
 
Screening evaluations will be performed only after the participant has provided written informed 
consent.  The following evaluations will be performed and information obtained up to 14 days 
before randomization and the start of study drug treatment: 
 
 Participant information and obtaining of written informed consent 
 Eligibility:  Assessment of inclusion and exclusion criteria (see Section 5.1) 
 Provide written information on local wound care 
 Take digital picture of the cardinal ulcer 
 Demographic data, including sex, race, ethnic group, year of birth, smoking history and 
alcohol consumption 
 Medical and surgical history 
 Prior and concomitant therapy 
 Physical examination, including height and weight 
 Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits in a sitting position after the subject has been at rest for at least 5 
minutes.  The same arm is always used for these measurements (See Section 7.6.4) 
 Digital ulcer assessment (see Section 7.6.5) 
 Provide 1-week diary to participant which they will complete daily for 7 consecutive 
days prior to Visit 1 to document Raynaud attacks (see Section 7.6.7) 
 Pregnancy test (urine) for all women of childbearing potential (see Section 7.6.1) 
 A standard 12-lead ECG will be obtained with the participant in the supine position after 
resting for at least 5 minutes 
 Hand x-rays for calcinosis 
 Blood samples for hematology, serum chemistry 
 
7.1.2.2 
Visit 1 – Baseline (Day 0, Week 0) – Double-Blind Treatment Phase 
 
The following assessments will be performed at the Baseline visit (Day 0 of study drug 
treatment): 
 
Before intake of study medication 
 
 Reconfirmation of eligibility 
 Discuss adherence with the local wound care 
 Take digital picture of the cardinal ulcer, if not done at screening visit 
 Patient reported outcomes (patient global assessment, PROMIS-29, and HAQ- D1/SHAQ 
and HDISS-DU) and physician global assessment 
 Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 


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measured at all visits in a sitting position after the participant has been at rest for at least 
5 minutes.  The same arm is always used for these measurements 
 Digital ulcer assessment 
 Assessment of Raynaud attacks – participant to return completed diary 
 Blood plasma sample for biomarkers to be obtained before the start of study drug 
treatment (see Section 7.6.3) 
 Pregnancy test (urine) for all women of childbearing potential (see Section 7.6.1) 
 Recording and assessment of AEs (see Section 7.5.1.3) 
 Concomitant therapy 
 Randomization to study drug treatment with either riociguat or placebo 
 Dispense study drug 
 
7.1.2.3 
Visits 2 through 7 – Dose titration/Stable dosing periods (Double-blind 
treatment phase) 
 
At these study visits, the participant should attend the clinic without having taken the morning 
dose of study medication. 
 
During the dose titration period and stable dosing periods of the double-blind treatment phase 
(Visits 2 to 7), the following assessments will be performed according to the schedule of events 
(Section 7.1.1): 
 
 Physical examination at Visits 3 and 7, including weight 
 Vital signs (blood pressure and heart rate) at every visit.  Blood pressure and heart rate 
will be measured at all visits in a sitting position after the participant has been at rest for 
at least 5 minutes.  The same arm is always used for these measurements 
 Discuss adherence with the local wound care at every visit 
 Take digital picture of the cardinal ulcer at week 7 
 Digital ulcer assessment at all visits 
 Recording and assessment of AEs at all visits 
 Pregnancy test (urine) for all women of childbearing potential at Visits 3, 5, 6, and 7 
 A standard 12-lead ECG will be obtained with the participant in the supine position after 
resting for at least 5 minutes at Visits 5 and 7 
 Hematology and serum chemistry at Visits 5 and 7 
 Patient reported outcomes (patient global assessment, PROMIS-29, HAQ- DI/SHAQ and 
HDISS-DU) and physician global assessment at Visit 7. 
 Assessment of Raynaud’s attacks – participant to be provided 1-week diary at Visit 6 and 
returned on Visit 7. Since the diary is only for 1 week, participant can do it for one 
continuous week between the 2 visits and bring it back at Visit 7. 
 Concomitant therapy at all visits 
 Dispensation of study drug (At Visit 7 if participant has active or painful indeterminate 
DU, Open Label drug will be dispensed if participant consents to continued participation 
in the study.)** Important note: Participants should not take the last dose of randomized 
drug the night prior to coming to the clinic for visit 7. 
 Blood plasma sample for biomarkers to be obtained before the start of study drug 


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treatment (see Section 7.6.3) at Visit 7 
 
7.1.2.4 
Early Termination Visit during Double Blind 
 
In the case of an early termination/withdrawal during double-blind period, follow the schedule of 
events for Visit 7. The only exception is that Raynaud’s diary is not collected if it was not 
dispensed at least 1 week prior to early termination visit. 
 
7.1.2.5 
Unscheduled visit 
 
Participants can be brought into the clinic for an unscheduled (UNSCH) visit should they 
experience dose toleration issues or other treatment related adverse events in between their 
regularly-scheduled visits. 
 
During an UNSCH visit, vitals, physical exam, and assessment for AE’s should occur. Should a 
dose reduction be warranted the participant should return the previously dispensed medication 
bottles.  The site can then dispense a lower dose through the drug dispensing system. 
 
7.1.2.6 
Visit  8 Safety Follow-up for double-blind period or start of Open-label 
 
If the participant does not qualify for or chooses not to participate in the open-label phase of the 
study at visit 7, they will return in 4 weeks for visit 8 which is intended to be a Safety Follow-up 
visit.  However, if at this time (visit 8), they have a DU and choose to enter the open-label phase, 
this visit is considered to be the start of the Open-Label phase (OLE Week 0) and they can 
receive study medication at this visit.  If at this time (visit 8), they don’t have DU, then this visit 
is the Week 20 Safety Follow-up (Visit 8).  If a participant does not have any adverse events that 
are attributable to the study medication [as assessed by the physician] the week 20 safety follow-
up can be performed over the phone, if the participant chooses, in order to minimize their 
burden.  
 
Week 20 Safety Follow-up (Visit 8) Procedures: 
 
 Concomitant therapy  
 Physical examination, including height and weight (if in-person visit) 
 Vital signs (blood pressure and heart rate).  (if in-person visit) 
 Discuss adherence with the local wound care if digital ulcers present 
 Digital ulcer assessment (if in-person visit) 
 Recording and assessment of AEs 
 
Open-Label phase (OLE Week 0) Visit 8 
 
 Physical examination including weight (not required if the participant returns with a DU 
within 7 days of completing the Visit 7) 
 Vital signs (blood pressure and heart rate).  
 Discuss adherence with the local wound care 
 Digital ulcer assessment 


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 Recording and assessment of AEs 
 Pregnancy test (urine) for all women of childbearing potential 
 A standard 12-lead ECG, (not required if the participant returns with a DU within 7 days 
of completing the Visit 7) 
 Hematology and serum chemistry (not required if the participant returns with a DU 
within 7 days of completing the Visit 7) 
 
7.1.2.7 
Visits 9 through 14 – Dose-titration phase/ Stable dosing periods (Open label 
extension phase) 
 
 Concomitant therapy at every visit 
 Physical examination, including height and weight (Visit 14) 
 Vital signs (blood pressure and heart rate) at every visit.  Blood pressure and heart rate 
will be measured at all visits in a sitting position after the participant has been at rest for 
at least 5 minutes.  The same arm is always used for these measurements 
 Discuss adherence with the local wound care at every visit 
 Digital ulcer assessment at all visits 
 Patient reported outcomes (patient global assessment, PROMIS-29, and HAQ- 
DI/SHAQ) and physician global assessment at Visit 14. 
 Hematology and blood chemistry Visits 12, and 14 
 Pregnancy test (urine) for all women of childbearing potential at Visits 10, 12, 13, and 
14. 
 A standard 12-lead ECG will be obtained with the participant in the supine position after 
resting for at least 5 minutes at Visits 9 and 14. 
 Recording and assessment of AEs  at every visit 
 Dispensation of open-label riociguat study drug at every visit up to and including Visit 13 
 Visit 14 will be the end of study visit. 
 
7.1.2.8 
Early Termination Visit during Open Label Extension 
 
In the case of an early termination/withdrawal during OLE, follow the schedule of events for 
Visit 14. 
 
7.2 
Population characteristics 
 
7.2.1 
Demographic 
 
The following demographic data will be recorded: 
 
 Date of birth (age) 
 Sex 
 Race and Ethnicity 
 Alcohol consumption 
 Smoking History 
 


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7.2.2. 
Medical history 
 
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected: 
 
 Pertaining to the study indication 
 Started before signing of the informed consent 
 Considered relevant to the study 
 Medical history related to concomitant therapy 
 
7.3 
Efficacy 
 
Primary efficacy outcome measure: 
 
 Change from baseline to end of the double-blind study treatment phase in digital ulcer net 
burden 
o Digital ulcer net burden is defined as the total number of “active” or 
“indeterminate” digital ulcers at that assessment. 
o Should be assessed as any ulcer including skin area distal to Metacarpophalangeal 
(MCP)  joint.. 
 
Secondary efficacy measures during double-blind period: 
 
 Healing of the cardinal DU 
 Time to healing of the cardinal DU 
 Time to healing of all DUs 
 Development of DU during the trial 
 Development/healing of ulcers over DIP, PIP, MCPs and elbows. 
 Improvement of Raynaud’s phenomenon 
o Raynaud’s condition score 
o Number of Raynaud’s attacks/day 
o Patient and physician assessment of RP; pain, numbness, and tingling during an 
RP attack; and duration of attacks 
 Patient’s and physician’s global assessment on a Likert scale 
 HRQOL using PROMIS-29 
 Physical function as assessed by HAQ-DI, and HDISS-DU 
 Visual analog scales from scleroderma-health assessment questionnaire (SHAQ) 
assessing burden of digital ulcers, Raynaud’s disease, gastrointestinal involvement, 
breathing, and overall disease 
 Digital ischemia requiring intravenous prostacyclin or digital gangrene or amputation 
 Vascular biomarkers in the plasma (VEGF, tPA, sE-Selectin, BFGF, VCAM-1, ICAM) 
 
Secondary efficacy measures during OLE period: 
 
 Healing of the cardinal DU 


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 Development of DU during the trial 
 Development/healing of ulcers over DIP, PIP, MCPs and elbows. 
 Patient’s and physician’s global assessment on a Likert scale 
 HRQOL using PROMIS-29 
 Physical function as assessed by HAQ-DI and HDISS-DU 
 Visual analog scales from scleroderma-health assessment questionnaire (SHAQ) 
assessing burden of digital ulcers, Raynaud’s disease, gastrointestinal involvement, 
breathing, and overall disease 
 Digital ischemia requiring intravenous prostacyclin or digital gangrene or amputation 
 
7.4 
Pharmacokinetics / pharmacodynamics 
 
Pharmacokinetics will not be performed in this study. 
 
7.5 
Safety 
 
7.5.1 
Adverse events 
 
7.5.1.1 
Definitions 
 
Definition of adverse event (AE) 
 
In a clinical study, an AE is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation participant after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
 
A surgical procedure that was planned prior to the start of the study by any physician treating the 
participant should not be recorded as AE (however, the condition for which the surgery is 
required may be an AE). 
 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory results, and 
ECG findings. 
 
 Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical history 
(e.g., seasonal allergy without acute complaints). 
 Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g., allergic pollinosis). 
 Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs. 
 
Definition of serious adverse event (SAE) 


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An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
 
a. Results in death 
 
b. Is life-threatening 
 
The term ‘life-threatening’ in the definition refers to an event in which the participant 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at 
least one of the following exceptions is met: 
 
- 
The admission results in a hospital stay of less than 12 hours 
- 
The admission is pre-planned 
(i.e., elective or scheduled surgery arranged prior to the start of the study) 
- 
The admission is not associated with an AE 
(e.g., social hospitalization for purposes of respite care). 
 
However, it should be noted that invasive treatment during any hospitalization may fulfill 
the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 
 
d. Results in persistent or significant disability / incapacity 
 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
 
e. Is a congenital anomaly / birth defect 
 
f. Is another medically important serious event as judged by the investigator 
 
7.5.1.2 
Classifications for adverse event assessment 
 
All AEs will be assessed and documented by the investigator according to the categories detailed 
below. 
 
7.5.1.2.1 Seriousness 
 
For each AE, the seriousness must be determined according to the criteria given in Section 
7.5.1.1 . 


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7.5.1.2.2 Severity 
 
The severity of an AE is classified according to the following categories: 
- 
Grade 1 Mild 
- 
Grade 2 Moderate 
- 
Grade 3 Severe 
- 
Grade 4 Very Severe 
- 
Grade 5 Death  
 
7.5.1.2.3 Causal relationship 
 
The assessment of the causal relationship between an AE and the administration of treatment is a 
clinical decision based on all available information at the time of the completion of the eCRF. 
 
The assessment is based on the question whether there was a “reasonable causal relationship” to 
the study treatment in question. 
 
Possible answers are “Related” or “Not Related” An assessment of “Not Related” would include: 
 
1. The existence of a clear alternative explanation, e.g., mechanical bleeding at surgical site. 
 
or 
 
2. Non-plausibility, e.g., the participant is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration. 
 
An assessment of “Related” indicates that there is a reasonable suspicion that the AE is 
associated with the use of the study treatment. 
 
Important factors to be considered in assessing the relationship of the AE to study treatment 
include: 
 
- 
The temporal sequence from drug administration: 
The event should occur after the drug is given.  The length of time from drug 
exposure to event should be evaluated in the clinical context of the event. 
- 
Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re- 
challenge): 
Participant’s response after de-challenge or participants response after re-challenge 
should be considered in the view of the usual clinical course of the event in 
question. 
- 
Underlying, concomitant, intercurrent diseases: 
Each event should be evaluated in the context of the natural history and course of 
the disease being treated and any other disease the participant may have. 
- 
Concomitant medication or treatment: 


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The other drugs the participant is taking or the treatment the participant receives 
should be examined to determine whether any of them may be suspected to cause 
the event in question. 
- 
The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and 
excretion) of the study treatment, coupled with the individual participant’s 
pharmacodynamics should be considered. 
 
Causal relationship to protocol-required procedure(s) 
 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s). 
 
Possible answers are “yes” or “no” 
 
7.5.1.2.4 Action taken with study treatment 
 
Any action on study treatment to resolve the AE is to be documented using the categories listed 
below. 
 
- 
Drug withdrawn 
- 
Drug interrupted 
- 
Dose reduced 
- 
Dose not changed 
- 
Not applicable 
- 
Unknown 
 
7.5.1.2.5 Other specific treatment(s) of adverse events 
 
- 
None 
- 
Remedial drug therapy 
- 
Other 
 
7.5.1.2.6 Outcome 
 
The outcome of the AE is to be documented as follows: 
 
- 
Recovered/resolved without sequelae 
- 
Recovered/resolved with sequelae 
- 
Not recovered/not resolved (ongoing) 
- 
Fatal 
- 
Unknown 
 
7.5.1.3 
Assessments and documentation of adverse events 
 


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The investigator has the obligation to report AEs. All non-serious events will be assessed and 
recorded during the specified observational phase (from signing the informed consent form up to 
30 [+5] days after last study medication intake), whether believed to be related or unrelated to 
the treatment. AE forms will be included in the eCRFs. The record will include clinical 
symptoms or final diagnosis when available, date of appearance, duration, severity and 
relationship to treatment. A record will also be kept of the action taken and the follow-up until 
resolution of the AE. 
 
7.5.1.4 
Reporting of serious adverse events 
 
Reporting of SAEs to the FDA 
 
The sponsor-investigator will report serious adverse event to the FDA according to the 
regulations found at 21 CFR 312.32. 
 
Notification of the IECs / IRBs 
 
Notification of the IECs / IRBs about all relevant events (e.g., SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the investigator according to all 
applicable regulations. 
 
Sponsor’s notification of the investigational site 
 
The sponsor will inform all investigational sites about reported relevant events (e.g., SUSARs) 
according to all applicable regulations. 
 
Sponsor Investigator reporting to Bayer 
 
All serious adverse events should be reported to the DCC who is responsible for reporting all 
serious adverse events that are unexpected and related to study medication to Bayer, the 
manufacturer of riociguat, within 24 hours. 
 
7.5.1.5 
Expected adverse events 
 
For this study, the applicable reference document is the most current version of the package 
insert. 
 
The expectedness of AEs will be determined by the sponsor according to the applicable reference 
document and according to all local regulations. 
 
7.5.1.6 
Adverse events of special safety interest 
 
Symptomatic hypotension and serious hemoptysis have been defined as AEs of special interest 
and must be documented accordingly in the corresponding AE eCRF.  Events of symptomatic 
hypotension and non-serious hemoptysis should not automatically be upgraded by the reporting 
Investigator to serious.  Declaration of an event as serious should only occur when 1 or more of 


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the serious criteria (as defined in Section 7.5.1.1 ) are applicable. 
 
7.5.1.7 
Overdose of Study Medication 
 
In case of overdose, standard supportive measures should be adopted as required.  In case of 
pronounced hypotension, active cardiovascular support may be required.  If symptoms develop 
after the investigational drug has been administered, any therapy that becomes necessary has to 
be guided by the predominant symptoms. Participants must remain under medical supervision 
until all relevant adverse effects have resolved in the event of overdose; participant continuation 
remains at the discretion of the investigator. 
 
7.5.2 
Pregnancies 
 
Riociguat is a category X drug and does come with a black box warning for embryo-fetal 
toxicity. Riociguat should not be administered to a pregnant female because it may cause fetal 
harm. For females of reproductive potential, pregnancy should be avoided before the start of 
riociguat treatment, during treatment, and for 1 month after stopping treatment. Pregnancy will 
be monitored with monthly urine pregnancy tests during treatment.  Acceptable methods of 
contraception should be used to prevent pregnancy during treatment and for one month after 
stopping treatment. 
 
The investigator must report to the sponsor any pregnancy occurring in a study participant during 
the participant’s participation in this study.  The report should be submitted within the same 
timelines as an SAE, although a pregnancy per se is not considered an SAE.  Any pregnancies 
should be reported to the DCC who is responsible for reporting to Bayer, the manufacturer of 
riociguat. 
 
For a study participant, the outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or the child should be reported. 
 
 


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7.6 
Other procedures and variables 
 
7.6.1 
Pregnancy testing 
 
Pregnancy testing is to be performed at the Screening Visit, Visit 1 (Day 0; urine) and in 4- 
weekly intervals thereafter (urine) until one month after the participant stops intake of study 
drug. The results are to be documented in the eCRF and in the patient file. 
 
In the event of pregnancy, study medication must be stopped and a referral to a gynecologist for 
confirmation of pregnancy must be organized as soon as possible.  In addition, the pregnancy 
must be reported to the sponsor as described in Section 7.5.2 and further consequences with 
regard to ongoing participation in the study must be discussed with the participant.  In the event 
uncertainties about a pregnancy test outcome exist, the participant should contact the site 
immediately to discuss further steps (e.g., exclusion of pregnancy by serum pregnancy test). 
 
Women of childbearing potential and non-vasectomized male participants must agree to use 
adequate contraception when sexually active. 
 
‘Adequate contraception’ is defined as any combination of at least 2 effective methods of birth 
control, of which at least one is a physical barrier (e.g., condoms with hormonal contraception or 
implants or combined oral contraceptives, certain intrauterine devices). 
 
7.6.2 
Laboratory parameters 
 
The laboratory parameters will be analyzed in a local laboratory and reported on the eCRF. 
 
7.6.3 
Exploratory Biomarkers 
 
Exploratory vascular biomarkers will be evaluated at Visit 1 (Day 0) and Visit 7 (Week 16). 
Plasma for determination of VEGF, tPA, sE-Selectin, BFGF, VCAM-1, and ICAM will be 
collected and shipped to the University of Michigan laboratory. Details on collection, processing 
and storage are described in the Manual of Operations. 
 
7.6.4 
Blood pressure and heart rate measurement 
 
Blood pressure and heart rate will be measured at all visits in a sitting position after the 
participant has been at rest for 5 minutes. The same arm is always used for these measurements. 
 
Methodology:  Noninvasive measurement preferably with a validated electronic device in 
accordance with published guidelines (e.g., American Heart Association Recommendations for 
Blood Pressure Measurement in Humans and Experimental Animals). 
 
7.6.5 
Digital ulcer net burden 
 


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Digital ulcers are defined as a full thickness skin lesion with loss of epithelium. Ulcers should be 
> 3mm in maximal diameter. Healing is defined by re-epithelialization with loss of pain and 
exudate. Pitting scars and hyperkeratotic lesions are always excluded. Also, eschar is not 
considered as a DU. 
 
Digital ulcer net burden will be assessed by the following methods: 
 
 Ulcer count – Ulcer assessment  will ideally be performed by the same physician at every 
visit: 
o Total ulcer counts distal to MCP joint (this can include both distal ulcer [defined 
as distal to PIP joint] and proximal ulcer [defined between MCP and PIP joint} 
o Distal (fingertip) ulcer counts:  any ulcer including skin area distal to proximal 
interphalangeal (PIP) joint 
 Ulcer net burden: Ulcer net burden is defined as the total number of “active” or 
indeterminate digital ulcers at that assessment.  Any ulcerfrom the  Metacarpophalangeal 
(MCP) joint to distal phalanges on the dorsal and palmar (volar) surface of the hand, 
(including the digital tip) and the elbows will be assessed. 
 Visual analog score for patient-reported severity of digital ulcers as part of the SHAQ 
(see section 7.6.8) 
 Non-ischemic ulcers over the dorsum of DIP, PIP, MCP and over elbows will also be 
evaluated for healing as secondary outcomes 
 
7.6.6 
Digital Gangrene 
 
Digital gangrene will be recorded as a separate event and may co-exist with digital ulcers that 
affect the same digit. 
 
Gangrene is defined as diffuse necrosis (pathologic death of deeper, e.g. subcutaneous, 
structures) due to obstruction, loss, or diminution of blood supply; it is of black color and 
painful, and may be localized to parts of the finger or involve an entire finger. It may be wet or 
dry, reflecting a degree of adjacent tissue perfusion, time course of necrosis and presence or type 
of associated secondary infection. 
 
7.6.7 
Raynaud’s attacks assessment 
 
Raynaud’s attacks will be assessed using the composite of the following 6 individual outcome 
measures in order to minimize the measurement variability and placebo response(7): Raynaud’s 
condition score, patient assessment of Raynaud’s phenomenon, physician assessment of 
Raynaud’s phenomenon, attack symptoms, duration of attacks, and number of attacks per day. 
 
The Raynaud’s condition score is a daily patient assessment of Raynaud’s phenomenon activity 
using a 0-10 ordinal scale. It incorporates the cumulative frequency, duration, severity and 
impact of Raynaud’s phenomenon attacks, reflecting the overall degree that Raynaud’s has 
affected use of the participant’s hands. The Raynaud’s condition score, along with details of the 
frequency and duration of Raynaud’s attacks, will be incorporated into the daily diary that 
participants will be asked to complete for 1 week (7 days) at the time points shown below. 


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The patient and physician assessment assesses the severity of Raynaud’s phenomenon in the past 
week using a 0-100 VAS. 
 
Frequency: Daily diary to be completed by participant for 7 consecutive days prior to study visits 
at Screening and Week 12. 
 
7.6.8 
Patient-Reported Outcomes (PROs) / Health-Related Quality of Life (HRQoL) 
questionnaires 
 
Three patient-reported outcomes (PROs)—the HAQ-DI/SHAQ, HDISS-DU and PROMIS-29—
will be completed by all participants in the study. 
 
Scleroderma Health Assessment Questionnaire (HAQ-DI/SHAQ) 
 
The HAQ-DI consists of 8 domains from the Health Assessment Questionnaire disability index, 
a HRQoL instrument that measures self-reported function in 8 domains of activity in 
20 weighted responses and a VAS of pain experienced in the past week.  It additionally measures 
5 domains specific to scleroderma using a continuous VAS:  Raynaud’s phenomenon, digital tip 
ulcers, lung symptoms, gastrointestinal symptoms, and a global patient assessment.  The VAS 
subscales of the SHAQ were shown to be significantly correlated with objective parameters and 
were responsive to change in a cohort and in a Raynaud’s phenomenon trial in SSc. The SHAQ 
requires approximately 5 minutes to complete. 
 
Hand Disability in Systemic Schlerosis-DU (HDISS-DU™) 
 
The HDISS-DU™ was developed in accordance with the 2009 guidance from the US Food and 
Drug Administration.The concepts and items comprising the HDISS-DU were developed based 
on an initial phase of interviews of digital ulcer (DU) patients that included concept elicitation 
and cognitive debriefing on the Cochin Hand Function Scale (an 18-item functional disability 
questionnaire that uses tasks of daily living to assess function), and a second phase of patient 
cognitive debriefing interviews on a revised instrument. Results from the cognitive debriefing 
interviews suggest that the draft HDISS-DU is a comprehensive measure assessing the impact of 
DUs on hand functioning that asks patients to rate their ability to complete common activities 
over the past 7 days. The psychometric evaluation, including final validation of the HDISS-DU 
and derivation of a scoring algorithm, is under development based on blinded data from the 
DUAL studies. The HDISS-DU requires approximately 5 minutes to complete. 
 
Patient-Reported Outcomes Measurement Information System (PROMIS)-29 
 
The PROMIS-29 is a validated instrument to measure the health status of SSc patients, 
demonstrating moderate to high correlation with other instruments validated in SSc, including 
the SF-36 physical component score and HAQ-DI. It incorporates 7 core domains from the 
PROMIS questionnaire, which specifically relate to physical, mental, and social health aspects of 
chronic illness:  pain, fatigue, depression, anxiety, sleep, and physical function, as well as one 
11-point rating scale for pain intensity.  It contains 8 items with 29 weighted responses in total, 


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and requires approximately 5 minutes to complete. 
 
7.6.9 
Participant and Physician Global Assessment 
 
A global assessment for patient and physician will be obtained. 
 
The participant assessment represents the patient’s assessment of the patient’s global 
scleroderma on a 0-10 Likert scale. “On a scale of 0-10, how was your overall health in the last 
week? 0=Excellent; 10=Extremely Poor.  The physician global assessment represents the 
physician’s assessment of the patient’s current disease activity on a 0-10 Likert scale. “On a 
scale of 0-10, how was your patient’s overall health in the last week? 0=Excellent; 10=Extremely 
Poor”. Both assessments are made at baseline and Week 16, OLE Week 0 and OLE Week 16. 
 
8. 
Statistical methods and determination of sample size 
 
8.1 
General considerations 
 
This section presents a summary of the planned statistical analyses.  A statistical analysis plan 
(SAP) will be written for the study that contains detailed descriptions of the analyses to be 
performed.  The SAP will be finalized prior to unblinding of the data. 
 
Continuous variables will be summarized using descriptive statistics including n, mean, median, 
standard deviation, range (e.g., minimum and maximum). Qualitative variables will be 
summarized using counts and percentages. Summaries will be provided by treatment group and 
overall.  Graphical methods will be heavily used in this pilot study to assess the pattern of 
response over time for key variables and to assess the relationships among variables. For most 
outcomes, separate analyses will be performed for the double-blind and open-label extension 
treatment periods. 
 
Unless otherwise specified, statistical analyses will be performed using SAS Version 9 or higher.  
Where appropriate, statistical tests will be conducted at the 0.05 significance level (with no 
adjustments for multiplicity) using two-tailed tests and p-values will be reported. 
 
Given the rare nature of SSc and the consequent small sample size for this pilot Phase IIa study, 
the statistical power of any comparisons is limited (i.e., there is sufficient power to detect only 
large treatment differences). As such the analysis will be largely descriptive in nature as the 
study is not powered to determine a statistical difference between riociguat vs. placebo.  The p-
values resulting from formal statistical tests will be interpreted from a hypothesis-generating, 
rather than a confirmatory framework. 
 
8.2 
Analysis sets 
 
The main population for efficacy will be the modified intention-to-treat population (MITT), 
defined as all participants randomized, receiving at least one dose of treatment, and having at 
least one post-baseline efficacy assessment. Participants will be analyzed by assigned treatment.   
The primary endpoint and all secondary outcomes will be assessed using this analysis set. 


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The Per Protocol population (PP) will consist of all participants in the MITT population who did 
not have a major protocol violation, inclusive of violation of entry criteria. Participants in this 
population will be referenced as evaluable.  Only the primary endpoint will be assessed using 
this analysis set (sensitivity analysis). 
 
The Safety Population is defined as all participants who were randomized and received at least 
one dose of the study drug. The Safety Population will be used for all safety analyses. 
Participants will be analyzed by treatment received. If participants inadvertently receive both 
active drug and placebo, they will be included in the riociguat group. 
 
Membership in the analysis populations will be determined before study unblinding. 
 
8.3 
Statistical and analytical plans 
 
8.3.1 
Demographic and other baseline characteristics 
 
Demographic variables and baseline characteristics will be summarized by treatment group. 
 
8.3.2 
Efficacy 
 
The primary endpoint is the mean change from baseline to end of the double-blind study 
treatment phase (Week 16) in the digital ulcer net burden. For the primary analysis, changes in 
digital ulcer net burden will be compared in the two treatment groups using an ANCOVA model 
with terms for treatment group and baseline digital ulcer net burden value. If the assumptions of 
this parametric model are not met, an alternative non-parametric model will be used. This model 
is based on the extension of the Wilcoxon rank-sum test to allow for covariate adjustment (9). 
This rank ANCOVA can provide additional power associated with baseline covariate adjustment, 
even when the outcome variable is not normally distributed 1(10). 
 
Analysis for secondary outcome measures that are continuous will be performed using a similar 
approach as that for the primary endpoint. We will compare the change in each secondary 
outcome measure from baseline to week 16 between the two treatment groups 
using an ANCOVA model or its non-parametric counterpart if the model assumptions aren’t met.  
Analyses of secondary outcomes measures that are discrete will be performed using Fisher’s 
exact tests. Analyses of secondary outcome measure that are counts will be performed using 
Poisson regression. 
 
8.3.3 
Safety 
 
Descriptive summary statistics for treatment-emergent adverse and serious adverse events will be 
reported. Adverse events will be grouped by body system and grade and will be tabulated as 
numbers and percentages; serious adverse events will be enumerated and described as 
appropriate. The total number of adverse events of each grade occurring in the two treatment 
groups by Week 16 will be compared using a Fisher’s exact test. Poisson regression or 
comparable non-parametric methods will be used to compare the total number of serious adverse 


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events during the double-blind 16-week period and (separately) during the open-label extension 
16-week period, by treatment group. Similar analyses will be conducted for treatment-emergent 
AEs and SAEs leading to discontinuation of study drug and of special safety interest. 
 
The other safety outcomes will be presented with descriptive statistics. 
 
The safety evaluation of laboratory data will include: 
 
 Incidence rates of treatment-emergent laboratory values outside of normal range. 
 Incidence rates of pre-specified laboratory data abnormalities. 
 Descriptive analysis of continuous laboratory parameters, and their changes from 
baseline by treatment group and visit. 
 
Descriptive analysis of vital signs, and their changes from baseline, will be performed by 
treatment group and visit. 
For ECGs, the status pre-treatment and post-treatment will be tabulated.  The incidence rates of 
treatment-emergent ECG abnormalities will be tabulated by treatment group.  A descriptive 
analysis of continuous ECG parameters and their changes from baseline by treatment group and 
visit will also be presented. 
 
8.4 
Planned interim analyses 
 
No formal interim analysis of the double-blind treatment phase is planned. 
 
8.5 
Determination of sample size 
 
SSc is a rare disease. The planned sample size of 20 SSc participants is based on practical 
considerations to obtain preliminary estimates of the magnitude of treatment differences in 
efficacy and safety rather than a desired power for a pre-specified difference as would be 
necessary for a confirmatory study. However, with this proposed sample of 20 participants (10 
riociguat and 10 placebo), we can calculate the magnitude of treatment differences (riociguat – 
placebo) for the primary efficacy endpoint – the change from baseline to end of double-blind 
treatment in digital ulcer net burden (a continuous endpoint), or safety outcomes – characterized 
by the proportion of participants who experience an AE.  There would be 80% power to detect an 
effect size (mean treatment difference divided by standard deviation) of 1.253 or greater with a 
two-sided type I error of 5% in the primary endpoint, based on a two- sample t test.  Given the 
pilot nature of this Phase IIa study, the difference between mean change in digital ulcer net 
burden between riociguat and placebo that can be detected with sufficient power is large.  
Similarly, we can calculate power for safety outcomes for this sample size:  there is 81% power 
to detect treatment differences of 51%, assuming 40% of placebo-treated participants experience 
an AE based on a two-sample binomial test. 
 
8.6 
Data recording 
 
It is the expectation of the sponsor that all data entered into the eCRF has source documentation 
available at the site. The site must implement processes to ensure this happens.  A source 


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document checklist will be used at the site to identify the source data for all data points collected 
and the monitor will work with the site to complete this. 
 
8.7 
Monitoring 
 
Given the enrollment period is dictated by seasonal considerations for DU incidence, we 
anticipate two monitoring visits per site during the course of the study. Once after the first 
subject has been randomized at the site and once after the study has closed to enrollment and all 
subjects have completed study visits. The frequency of monitoring visits may be adjusted 
throughout the life cycle of the study as study conditions and needs evolve. Additional visits can 
be scheduled at the request of the Study Team or DSMB. 
 
The Clinical Research Monitor will ensure that: 
 
 Data collected and entered into the database are verifiable against source documents for 
the randomized participants 
 Appropriate consent is obtained for each participant prior to study procedures 
 Safety and rights of participants are being protected 
 Study is conducted in accordance with the currently approved protocol (including study 
treatment being used in accordance with the protocol) 
 Study medication is properly dispensed and accounted for 
 Any other study agreements, GCP, and all applicable regulatory requirements are met. 
 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
 
8.8 
Archiving 
 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
 
Participant (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where the 
archiving procedures do not meet the minimum timelines required by the sponsor, alternative 
arrangements must be made to ensure the availability of the source documents for the required 
period. 
 
The investigator/institution notifies the sponsor if the archival arrangements change (eg, 
relocation or transfer of ownership). 
 
The investigator site file is not to be destroyed without the sponsor’s approval. 
 
The contract with the investigator/institution will contain all regulations relevant for the study 
center. 
 
9. 
Premature termination of the study 


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The sponsor (Dr. Khanna) has the right to close this study (or, if applicable, individual segments 
thereof [e.g., treatment arms; dose steps; centers]) at any time, which may be due but not limited 
to the following reasons: 
 
 If risk-benefit ratio becomes unacceptable owing to, for example, 
- 
Safety findings from this study (e.g., SAEs) 
- 
Results of any interim analysis 
- 
Results of parallel clinical studies 
- 
Results of parallel animal studies (e.g., toxicity, teratogenicity, carcinogenicity or 
reproduction toxicity). 
 If the study conduct (e.g., recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame. 
 
The investigator has the right to close his/her center at any time. 
 
For any of the above closures, the following applies: 
 
 Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing. 
 All affected institutions (e.g., IEC(s)/IRB(s); competent authority (-ies); study center; 
head of study center) must be informed as applicable according to local law. 
 All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until notification 
given by the sponsor for destruction. 
 In case of a partial study closure, ongoing participants, including those in post study 
follow-up, must be taken care of in an ethical manner. 
 
Details for individual participant's withdrawal can be found in Section 5.2.1. 
 
10. 
Ethical and legal aspects 
 
10.1 
Ethical and legal conduct of the study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the sponsor and investigator abide by GCP guidelines 
and under the guiding principles detailed in the Declaration of Helsinki.  The study will also be 
carried out in keeping with applicable local law(s) and regulation(s). 
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol. 
 
Investigators may implement a protocol change after discussing the details and getting IRB 
approval. Any deviations from the protocol must be explained and documented by the 
investigator. 


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Details on discontinuation of the entire study or parts thereof can be found in Section 9. 
 
10.2 
Compensation for health damage of participants / insurance 
 
This is an investigator-initiated study. Therefore, compensation will be provided per local 
hospital policies or by participant’s medical insurance. There is no compensation provided by the 
sponsor or Bayer. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11. 
Appendices 
 
11.1 
Child-Pugh Classification of Liver Disease 
 
Factor 
+1 
+2 
+3 
Bilirubin (mg/dL) 
< 2 
2 – 3 
> 3 
Albumin (g/dL) 
< 2.8 
2.8 – 3.5 
> 3.5 
INR 
< 1.7 
1.7 – 2.3 
> 2.3 
Ascites 
None 
Mild 
Moderate / Severe 
Encephalopathy 
None 
Grade II – III or 
medically controlled 
Grade III – IV or 
poorly controlled 
 
Child-Pugh Class 
A 
B 
C 
Points 
5 -6 
7 – 9 
10 - 15 
 
INR = International Normalized Ratio. 
Source: Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for 
bleeding oesophageal varices. Br J Surg 1973;60:646-649 
 
11.2 
Digital Ulcer Care Protocol 
 
Digital Ulcer Care protocol: 
 
Active ulcers: 
 
Clean the ulcer once daily. This can be done by either soaking or gently washing the ulcer with sterile 
normal saline (this can be bought from any drug store).   Allow the ulcer to air-dry or pat-dry using a 
sterile gauze. 
 
Apply vitamin E oil once daily. This should be done by dropping the oil on to the sterile gauze which will 
be covering the wound. The gauze will then be placed over the ulcer, and secured by either 3M™ Coban 
(sold as breathable gentle tape), absolute waterproof tape (sold by Nexcare or local pharmacy brand) or a 
Band-Aid. 
 
 


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Dressings should be changed at least once daily.  If the ulcer appears macerated the option of 
leaving the wound open at night may be considered. 
Indeterminate ulcers with significant eschar/crust formation (no longer open): 
 
Ulcers should continue to be cleaned once daily.  AT this time either sterile normal saline or 
sterile water may be used by either soak or gentle washing. 
 
When eschar/crust forms, hydrogen peroxide once daily should be used (to help remove eschar 
formation).  The 3% hydrogen peroxide solution can be used by soaking or applying with a 
sterile q- tip, depending on the size of the ulcer. Add 1 table spoon of hydrogen peroxide solution 
in 5 table spoons of water (1:5 concentration). 
 
 
 
 
 
 
 
 
 
 
 
At this stage the ulcer may be kept clean and dry overnight. During activities a dressing of gauze 
and secured by either Coban, Nexcare waterproof tape or a Band-Aid may be used to protect the 


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wound. 
 
You may continue with vitamin E oil applied one daily.  In this case the vitamin E oil can be 
applied directly to the ulcer. 
 
Debridement should not be performed during the double-blind phase of the study unless it is 
clinically indicated.  (e.g., for treatment of an infection.)    
 
 


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12. 
References 
 
1. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 
classification criteria for systemic sclerosis: an American College of 
Rheumatology/European League against Rheumatism collaborative initiative. Arthritis 
Rheum. 2013 Nov;65(11):2737-47. 
2. Tingey T, Shu J, Smuczek J, Pope J. Meta-analysis of healing and prevention of digital ulcers 
in systemic sclerosis. Arthritis Care Res (Hoboken). 2013 Sep;65(9):1460-71. 
3. Beyer C, Reich N, Schindler SC, Akhmetshina A, Dees C, Tomcik M, et al. Stimulation of 
soluble guanylate cyclase reduces experimental dermal fibrosis. Ann Rheum Dis. 2012 
Jun;71(6):1019-26. 
4. Beyer C, Zenzmaier C, Palumbo-Zerr K, Mancuso R, Distler A, Dees C, et al. Stimulation of 
the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non- canonical TGFbeta 
signalling. Ann Rheum Dis. 2014 Feb 23. 
5. Geschka S, Kretschmer A, Sharkovska Y, Evgenov OV, Lawrenz B, Hucke A, et al. Soluble 
guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in 
salt-sensitive Dahl rats. PLoS One. 2011;6(7):e21853. 
6. Sharkovska Y, Kalk P, Lawrenz B, Godes M, Hoffmann LS, Wellkisch K, et al. Nitric oxide-
independent stimulation of soluble guanylate cyclase reduces organ damage in experimental 
low-renin and high-renin models. J Hypertens. 2010 Aug;28(8):1666-75. 
7. Gladue H, Maranian P, Paulus H, Khanna D. Evaluation of test characteristics for outcome 
measures used in Raynaud's phenomenon clinical trials. Arthritis Care Res (Hoboken). 2013 
Apr;65(4):630-6. 
8. Merkel PA, Herlyn K, Martin RW, Anderson JJ, Mayes MD, Bell P, et al. Measuring disease 
activity and functional status in patients with scleroderma and Raynaud's phenomenon. 
Arthritis Rheum. 2002;46(9):2410-20. 
9. Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical data analysis. In: Berry 
DA, ed. Statistical Methodology in the Pharmaceutical Sciences. New York, NY: Marcel 
Dekker; 1990:389–473. 
10. LaVange LM, Durham TA, Koch GG. Randomization-based nonparametric methods for the 
analysis of multicentre trials. Stat Methods Med Res. 2005;14:281– 301 

SAP_001.pdf: 
Statistical Analysis Plan 
 
 
 
 
 
RESCUE 
RESCUE SAP – FINAL 
14SEP2018 
Page 1 of 21 
 
 
RESCUE Statistical Analysis Plan 
 
TRIAL FULL TITLE 
A MULTI-CENTER RANDOMIZED, DOUBLE-BLIND, PLACEBO- 
CONTROLLED PILOT STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF RIOCIGUAT IN SCLERODERMA-ASSOCIATED 
DIGITAL ULCERS 
SAP VERSION 
FINAL 
SAP VERSION DATE 
22AUG2018 
TRIAL STATISTICIAN 
Cathie Spino, DSc 
Protocol Version (SAP 
associated with) 
Protocol Version 4 
July 10, 2017 
TRIAL PRINCIPAL 
INVESTIGATOR 
Dinesh Khanna, MD, MS 
SAP AUTHOR(s) 
Cathie Spino, DSc 
 
1 SAP Signatures 
I give my approval for this SAP entitled “ASSET Statistical Analysis Plan,” dated 14SEP2018. 
 
Statistician (Author) 
Name:   Cathie Spino, ScD 
 
 
 
Signature:
 
 
Date: 
14AUG2018 
 
 
 
 
Principal Investigator 
Name:  Dinesh Khanna, MD, MS 
 
Signature: 
 
 
Date: 
22AUG2018 
  
 
 
 


Statistical Analysis Plan 
 
 
 
 
 
RESCUE 
RESCUE SAP – FINAL 
14SEP2018 
Page 2 of 21 
2 Table of Contents 
1 
SAP Signatures 
1 
2 
Table of Contents 
2 
3 
Introduction 
4 
3.1 
Preface 
4 
3.2 
Scope of the analyses 
4 
4 
Study Objectives and End points 
4 
4.1 
Study Objectives 
4 
4.2 
End points 
5 
5 
Study Methods 
8 
5.1 
General Study Design and Plan 
8 
5.2 
Inclusion-Exclusion Criteria and General Study Population 
8 
5.2.1 
Inclusion Criteria 
8 
5.2.2 
Exclusion Criteria 
9 
5.3 
Randomization and Blinding 
10 
5.4 
Study Assessments 
10 
5.5 
Imputation of Dates 
13 
6 
Sample Size 
14 
7 
General Analysis Considerations 
15 
7.1 
Timing of Analyses 
15 
7.2 
Analysis Populations 
15 
7.2.1 
Modified Intention to Treat Population 
15 
7.2.2 
Per Protocol Population 
15 
7.2.3 
Safety Population 
15 
7.3 
Covariates and Subgroups 
15 
7.3.1 
Multi-center Studies 
15 
7.4 
Missing Data 
16 
7.5 
Interim Analyses and Data Monitoring 
16 
7.6 
Multiple Testing 
16 
8 
Summary of Study Data 
16 
8.1 
Subject Disposition 
16 
8.2 
Protocol Deviations 
17 
8.3 
Demographic and Baseline Variables 
17 
8.4 
Treatment Compliance 
17 
9 
Efficacy Analyses 
17 
9.1 
Primary Efficacy Analysis 
17 
9.2 
Secondary Efficacy Analyses 
18 
9.2.1 
Secondary Analyses of Primary Efficacy End point 
18 
9.2.2 
Analyses of Secondary End points 
18 


Statistical Analysis Plan 
 
 
 
 
 
RESCUE 
RESCUE SAP – FINAL 
14SEP2018 
Page 3 of 21 
10 Safety Analyses 
18 
10.1 
Adverse Events 
18 
10.2 
Deaths, Serious Adverse Events and other Significant Adverse Events 
19 
10.3 
Pregnancies 
19 
10.4 
Clinical Laboratory Evaluations 
19 
10.5 
Extent of Exposure 
19 
10.6 
Prior and Concurrent Medications 
20 
10.7 
Other Safety Measures 
20 
11 Reporting Conventions 
20 
12 Summary of Changes to the Protocol and/or SAP 
20 
15 References 
21 
16 Listing of Tables, Listings and Figures 
21 
 
 
 


Statistical Analysis Plan 
 
 
 
 
 
RESCUE 
RESCUE SAP – FINAL 
14SEP2018 
Page 4 of 21 
 
 
3 Introduction 
 
3.1 Preface 
Systemic sclerosis (SSc) is a rare, orphan disease featuring chronic, fibrosing, autoimmune responses 
characterized by small vessel vasculopathy, autoantibody production, and fibroblast dysfunction 
leading to increased deposition of extracellular matrix. 
 
Systemic sclerosis is further divided into 2 subtypes defined by the extent of skin involvement: 
limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc). dcSSc 
is one of the most fatal rheumatic diseases, and is associated with substantial morbidity and many 
detrimental effects on health-related quality of life. 
 
Raynaud’s phenomenon (RP) is an almost universal manifestation of SSc, with 95% of all patients 
being affected, and resulting in digital ulcers (DUs) in approximately 30% of the patients each year. 
DUs are a major clinical problem, being associated with substantial morbidity (reduced quality of life, 
pain, disability and disfigurement) that can escalate to gangrene and amputation in approximately 
15% of patients. Treatments that have shown potential include calcium channel blockers, prostacyclin 
analogues and endothelin receptor antagonists (ERAs). 
 
Riociguat is the first-in-class of a new group of compounds, soluble guanylate cyclase (sGC) 
stimulators. Riociguat directly stimulates sGC, thereby increasing levels of the signaling molecule 
cGMP. The cGMP molecule plays a pivotal role in regulating cellular processes, such as vascular 
tone, proliferation, fibrosis, and inflammation. Two key features of riociguat are (i) it directly 
stimulates sGC independently of nitric oxide (NO), and (ii) it sensitizes sGC to low levels of NO.  
Riociguat has recently been approved in the US and Canada for two forms of pulmonary 
hypertension, namely pulmonary arterial hypertension (PAH) and treatment of chronic 
thromboembolic pulmonary hypertension (CTEPH). 
 
The goal of the current study is to provide preliminary data on the efficacy and safety of 16 weeks of 
treatment with riociguat in a randomized, placebo-controlled clinical trial in patients with SSc-
associated DU. 
 
3.2 Scope of the analyses 
These analyses will assess the efficacy and safety of riociguat in comparison with placebo during the 
16-week  double-blind period, addressing the primary and secondary objectives of study through the 
double-blind period.  The objectives associated with the open-label extension period are not included 
in this SAP.   
 
4 Study Objectives and End points 
 
4.1 Study Objectives 
 
Primary Objectives 
 
To provide preliminary data on the efficacy (digital ulcer net burden) of riociguat administered 
3 times daily (TID) in comparison to placebo in patients with SSc. 
 
Secondary Objectives 
 
To provide preliminary data on safety and additional measures of efficacy of riociguat 
administered TID as compared with placebo. 
 


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4.2 End points 
 
4.2.1 
Primary Efficacy End point 
Change from baseline to end of double-blind treatment (week 16) in digital ulcer net burden.  Digital 
ulcer net burden is defined as the total number of “active” and indeterminate digital ulcers at an 
assessment.   
 
4.2.2 
Secondary Efficacy End points 
 
Proportion of participants with healing of their cardinal DU by week 16. For each participant, 
one digital ulcer must be identified and designated by the investigator as the cardinal ulcer at 
screening. The cardinal ulcer must have met the qualifications for designation as an active or 
painful indeterminate ulcer. If only one ulcer was determined at entry to be active or painful 
indeterminate, it will be designated as the cardinal ulcer. If several digital ulcers qualified, the 
cardinal ulcer could be either the largest or the most painful ulcer, or the ulcer that disturbed 
the patient the most. The cardinal ulcer will be selected by the investigator based on the clinical 
judgment that it was amenable to and evaluable for healing.   Cardinal ulcers are considered 
healed when classified as ‘healed’ and not ‘active’ or ‘indeterminate’ by week 16. 
 
Proportion of participants with healing of all DUs at baseline by week 16.  Baseline DUs are 
considered healed when classified as ‘healed’ and not ‘active’ or ‘indeterminate’ by week 16. 
All baseline ulcers must be healed for the participant to be classified as having all baseline 
ulcers healed.  Note that this end point does not consider whether a participant develops new 
DUs during the course of the study. 
 
Proportion of participants with no DUs at week 16.  This end point does not consider the 
number of ulcers at baseline or during the course of the study; only the absence of ‘active’ and 
‘indeterminate’ DUs at week 16.   
 
Proportion of participants with and number of new active and indeterminate DU(s) over the 
course of the double-blind period.   
 
Proportion of participants who develop pressure ulcers by location -- Distal 
Interphalangeal (DIP), Proximal Interphalangeal (PIP), Metacarpophalangeal 
(MCPs) and elbows – over the course of the double-blind period. 
 
Proportion of participants with healing of all pressure ulcers by location -- Distal 
Interphalangeal (DIP), Proximal Interphalangeal (PIP), Metacarpophalangeal 
(MCPs) and elbows –by the  course of the double-blind period. Note that this is 
defined among those who had pressure ulcer(s) at a certain location at baseline or 
who had one develop during the course of the double-blind treatment period. 
 
Time to healing of cardinal DU, defined as the number of weeks from randomization to the 
earliest of healing, end of the double-blind period, or drop-out.  Participants are censored if 
they drop-out or their cardinal DU has not healed by the end of the double-blind period. 
 
Time to healing of all baseline DU, defined as the number of weeks from randomization to 
the earliest of all baseline DU(s) healed, end of the double-blind period, or drop-out.  
Participants are censored if they drop-out or all of their baseline DU(s) have not healed by the 
end of the double-blind period. 
 
Time to development of new (‘active’ or ‘indeterminate’) DU during the double-blind period 
of the trial, defined as the number of weeks from randomization to the earliest of new DU, 
end of the double-blind period, or drop-out. Participants are censored if they drop-out or have 
not developed a new DU by the end of the double-blind period.  
 
Improvement of Raynaud’s phenomenon (RP).  A diary is completed by each participant to 
collect daily RP information.  Each characteristics is reported by the participant daily for at 
least 7 consecutive days during the screening phase and at least 7 consecutive days in the 2 
weeks between the week 12 and week 16 visits.  If less than 7 days are marked, then the 
average is calculated by accounting by the days where diary is completed (included the days 
where participants have no RP attack). 
o Raynaud’s condition score.  The score ranges from 0 to 10 and indicates the difficulty 
the participant had with their Raynaud’s condition.  The mean score will be 


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calculated across the 7-day screening and week 16 periods for each participant. 
o Number of Raynaud’s attacks/day.  The mean number of Raynaud’s attacks each day 
will be calculated across the 7-day screening and week 16 periods for each 
participant. For the days when a participant does not have an attack, a score of 0 will 
be used.   
o Duration of attacks.  For the days when a participant does not have an attack, a score 
of 0 will be used.  The mean duration of attacks (in minutes) will be calculated across 
the 7-day screening and week 16 periods for each participant. 
o Patient assessment of RP: pain, numbness, and tingling during an RP attack.  Patient 
assessments of RP pain, numbness and tingling symptoms are reported on a 0-100 
scale.  For the days when a participant does not have an attack, a score of 0 will be 
used.  The mean scale score for each symptom will be calculated across the 7-day 
screening and week 16 periods for each participant. 
 
Physician assessment of RP:  
o Severity of patient’s Raynaud’s disease. The mean response on a 0-10 Likert scale 
will be calculated.   
o Severity of patient’s digital ulcer(s). The mean response on a 0-10 Likert scale will 
be calculated.   
o Change in patient’s digital ulcers at Week 16.  Physician’s responses to the question 
“At Week 16, compared to the start of the trial do you consider your patient’s digital 
ulcer(s)” as much better | a little better | no change | a little worse | much worse will 
be summarized as a categorical variable.   
o Change in patient’s Raynaud’s disease at Week 16.  Physician’s responses to the 
question “At Week 16, compared to the start of the trial do you consider your 
patient’s Raynaud’s disease” as much better | a little better | no change | a little 
worse | much worse will be summarized as a categorical variable. 
 
Patient assessment of RP:  
o Severity of Raynaud’s disease. The mean response on a 0-10 Likert scale will be 
calculated.   
o Severity of digital ulcer(s). The mean response on a 0-10 Likert scale will be 
calculated.   
o Change in digital ulcers at Week 16.  Patient’s responses to the question “Compared 
to START OF THE TRIAL, do you consider that your digital ulcer(s) is:” as much 
better | a little better | no change | a little worse | much worse will be summarized as 
a categorical variable.   
o Change in Raynaud’s disease at Week 16.  Patient’s responses to the question 
“Compared to START OF THE TRIAL, do you consider that your Raynaud's 
disease is:” as much better | a little better | no change | a little worse | much worse 
will be summarized as a categorical variable. 
 
Change from baseline to each follow-up week in:   
o Patient’s global assessment for overall disease.  Patient global assessment for overall 
disease: This assessment represents the patient’s assessment of the patient’s global 
scleroderma on a 0-10 Likert scale. “On a scale of 0-10, how was your overall health 
in the last week? 0=Excellent; 10=Extremely Poor.  
o Physician’s global assessment for overall disease. Physician global assessment for 
overall disease:  This assessment represents the physician’s assessment of the 
patient’s current disease activity on a 0-10 Likert scale. “On a scale of 0-10, how was 
your patient’s overall health in the last week? 0=Excellent; 10=Extremely Poor”.  
o PROMIS-29 Profile v2.0 measures in the following domains:  physical function, 
anxiety, depression, fatigue, sleep disturbance, pain interference, and ability to 
participate in social roles and activities, and a single item on pain intensity.  
PROMIS-29 Profile v2.0 measure:  The National Institutes of Health (NIH) Patient-
Reported Outcomes Measurement Information System (PROMIS®) Roadmap 
initiative (www.nihpromise.org) is a cooperative research program designed to 


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develop, evaluate, and standardize item banks to measure patient-reported outcomes 
(PROs) across different medical conditions as well as the US population. PROMIS-
29 Profile v2.0 measure contains 29 items, which includes four items each from 
physical function, anxiety, depression, fatigue, sleep disturbance, pain interference, 
and satisfaction with social roles domains, and a single item on pain intensity. With 
the exception of physical function which does not include a time frame, all item 
banks reference the past 7 days.  Three scores are available for each PROMIS 
domain:  cumulative score, instrument score and transformed score; the transformed 
score (Tscore) will be the score analysed in this study.   
o  HAQ-DI overall (HAQ-DI) and 8 categories: Dressing and Grooming, Hygiene, 
Arising, Reach, Eating, Grip, Walking, Common Daily Activities (IADL).  The 
SHAQ consists of the HAQ-DI (8 domains and an overall score) and 6 visual 
analogue scales assessing the burden of pain, digital ulcers, Raynaud’s, 
gastrointestinal involvement, breathing, and overall disease. The HAQ-DI is a 
disease-targeted, musculoskeletal-targeted measure intended for assessing functional 
ability in arthritis. It is a self-administered 20-question instrument that assesses a 
patient’s level of functional ability and includes questions that involve both upper and 
lower extremities. The score for each question ranges from 0 (no disability) to 3 
(severe disability). There are 8 categories and an overall score (HAQ-DI).  It has a 7-
day recall period and has been extensively used in SSc.  
o Composite score for hand function.  The sum of the individual scores for dressing, 
hygiene, and grip from the HAQ-DI will be calculated.  These categories are 
associated with hand function.   
o The Hand Disability in Systemic Sclerosis-DU (HDISS-DU).  Participants were 
asked to answer 24 questions on the use of the hand(s) affected by DUs over the past 
7 days on a 6-point scale from scored from 1–6 (1=yes, without difficulty; 2=yes, 
with a little difficulty; 3=yes, with some difficulty; 4=yes with much difficulty; 
5=nearly impossible to do & used unaffected hand only; 6=impossible). Note that 
“used unaffected hand only” should be rescored to 5. The response option of “Did not 
do this activity in the past 7 days” will be scored as missing. The total HDISS-DU® 
score is calculated as a mean of valid items, with a total number of possible valid 
items equal to 24; higher scores represent increased disability in hand functioning. 
For missing items/values, the average score will be calculated out of the number of 
valid items; for example, if three items are missing from the questionnaire, the 
average will be calculated as the sum of the 21 valid items divided by 21. 
o Scleroderma-HAQ-DI visual analogue scales (VAS) assessing burden of digital 
ulcers, Raynaud’s disease, gastrointestinal involvement, breathing, and overall 
disease. 
 
Proportion of participants who experience digital ischemia requiring intravenous prostacyclin 
or digital gangrene or amputation during the trial. 
 
Proportion of participants who develop osteomyelitis during the trial 
 
Changes in vascular biomarkers in the plasma (VEGF, tPA, sE-Selectin, BFGF, VCAM-1, 
ICAM) from baseline to week 16.  Change is defined as (1) the absolute difference (week 16 
– baseline value) and as (2) the proportion of participants whose values are > 2 standard 
deviations from the mean, based on a population of healthy volunteers who are matched on 
sex and age to those from the RESCUE study. 
 
4.2.3 
Secondary Safety End points 
 
Adverse  events 
 
Adverse events of special interest:  symptomatic hypotension; serious haemoptysis 
 
Clinically  significant  changes in vital  signs 
 
Laboratory test abnormalities.  In general, for quantitative laboratory values reported as “<” 
or “≤” the lower limit of quantitation (LLOQ) or limit of detection (LOD), one‐half of the 
reported value (i.e., LLOQ/LOD) will be used for analysis. For quantitative laboratory values 


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reported as “>” or “≥” the upper limit of quantitation (ULOQ), the reported value (i.e., 
ULOQ) will be used for analysis.  The number and percentage of subjects with values < or > 
limits of quantitation or detection will also be provided. 
 
For analysis purposes, repeat laboratory test results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non‐missing repeat 
laboratory value will be used for data analysis. 
 
Clinical tolerability of the drug 
 
5 Study Methods 
 
5.1 General Study Design and Plan 
This clinical trial is a US, multicenter, double-blind, randomized placebo-controlled, parallel- group 
study with a total of 20 participants planned to be randomized (approximately 10 participants to the 
riociguat group and 10 to the placebo group). In addition, a standardized wound care protocol (see 
Appendix 11.2) will be followed by the investigators and digital photography will be taken of the 
cardinal ulcer. 
 
The study will allow standard of care medications for the management of DU as background therapy. 
These may include calcium channel blockers, low dose aspirin, angiotensin enzyme inhibitors, etc. 
and will be determined by the participant’s local physician. 
 
The schema below describes the main elements of the study design: 
 
 
5.2 Inclusion-Exclusion Criteria and General Study Population 
 
5.2.1 
Inclusion Criteria 
1. 
Signed written informed consent 
2. 
Men or women aged 18 years and older 
3. 
Diagnosis of Systemic sclerosis, as defined by 2013 American College of Rheumatology/ 
European Union League Against Rheumatism classification of SSc 
4. 
Patients had to have at least one visible, active ischemic DU or painful indeterminate DU   at 
screening located at or distal to the proximal interphalangeal joint, and that developed or 
worsened within 8 weeks prior to screening.   
5. 
Females of reproductive potential (FRP) must have a negative, pre-treatment urine pregnancy 
test. 


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6. 
FRP must obtain monthly urine pregnancy tests during treatment and one month after 
treatment discontinuation.  Post-menopausal women (defined as no menses for at least 1 year 
or post-surgical from bilateral oophorectomy) are not required to undergo a pregnancy test. 
7. 
FRP and all non-vasectomized male participants must agree to use reliable contraception 
when sexually active. (For FRP’s,  ‘Adequate contraception’ is defined as any combination 
of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g., 
condoms with hormonal contraception or implants or combined oral contraceptives, certain 
intrauterine devices). This applies from the time of signing the informed consent form until 
one month after the last study drug administration.) 
8. 
Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent), nonsteroidal anti- 
inflammatory drugs (NSAIDs), angiotentin receptor blockers, angiotensin converting enzyme 
(ACE) inhibitors and calcium channel blockers are permitted if the participant is on a stable 
dose for ≥ 2 weeks prior to and including the baseline visit 
9. 
Ability to comply with the clinical visits schedule and the study-related procedures. 
 
 
5.2.2 
Exclusion Criteria 
1. Active DU related to calcinosis (as assessed by clinical examination or radiographic evaluation 
at screening) 
2. Medical and surgical history 
 
Major surgery (including joint surgery) within 8 weeks prior to screening 
 
Participants with a history of malignancy in the last 5 years other than non-melanoma skin 
cell cancers cured by local resection or carcinoma in situ 
3. Hepatic-related criteria 
 
Hepatic insufficiency classified as Child-Pugh C at screening (see Appendix 11.1 for 
classification table) at screening visit 
4. Renal-related criteria 
 
Estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73m2 (MDRD formula) or on 
dialysis at the screening visit 
5. Cardiovascular-related criteria 
 
Sitting systolic blood pressure < 95 mmHg at the screening visit 
 
Sitting heart rate < 50 beats per minute (BPM) at the screening visit 
 
Left ventricular ejection fraction < 40% prior to screening on echocardiogram done as part 
of clinical care 
6. Pulmonary-related criteria 
 
Active state of hemoptysis or pulmonary hemorrhage, including those events managed by 
bronchial artery embolization 
 
Any history of bronchial artery embolization or massive hemoptysis within 3 months prior 
to screening. Massive hemoptysis being defined as acute bleeding >240 mL in a 24-hour 
period or recurrent bleeding >100 mL/d over several days 
 
PAH requiring pharmacologic therapy. 
 
Significant pulmonary disease with FVC ≤ 50% of predicted, or DLCO (uncorrected for 
hemoglobin ) ≤ 40% of predicted 
7. Laboratory examinations 
 
Participants with hemoglobin < 9.0 g/dL, white blood cell (WBC) count < 3000/mm3 (< 3 
× 109/L), platelet count < 100,000/mm3 (< 3 × 109/L) at the screening visit 
8. Prior and concomitant therapy 
 
Concomitant use of nitrates or NO donors (such as amyl nitrate) in any form, including 
topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as sildenafil, tadalafil, 
vardenafil); and nonspecific PDE5 inhibitors (theophylline, dipyridamole).  If the patient 
is on PDE5 inhibitors, a wash out of 3 days is required for sildenafil and 7 days for tadalafil 
or vardenafil prior to the baseline visit 
 
Concomitant Endothelin receptor antagonist 


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 
Patients who are actively smoking at time of consent. (Quit date of two weeks prior to 
screening acceptable) 
9. Pregnant or breastfeeding women 
10. Other 
 
Any other condition or therapy that would make the participant unsuitable for this study 
and will not allow participation for the full planned study period 
 
Participation in another clinical study with an investigational drug or medical device within 
30 days prior to randomization (phase I-III clinical studies) 
 
Note: One re-assessment of laboratory parameters is allowed during the screening phase to assess the 
eligibility of participants. 
 
5.3 Randomization and Blinding 
At the baseline visit, participants who met all of the inclusion and none of the exclusion criteria were 
randomized in 1:1 fashion to riociguat or placebo using a web-based randomization system.  At the 
time of randomization, patients were assigned a unique randomization number; no participant was to 
begin treatment prior to randomization.  The DCC prepared the randomization schedule, using 
computer-generated block randomization with the block size(s) known only by the DCC.  A secure 
web-based application was built for use by the coordinators to enter participant information (e.g., 
participant ID, stratification factor(s)) and to obtain the randomization number.  The coordinators 
printed the randomization # and bottle assignment information from this system and sent the 
information to the research pharmacy for dispensing.  The study was conducted in double-blind 
fashion.  Active riociguat and placebo tablet formulations were identical in appearance (size, shape, 
color) and smell.  The packaging and labeling was designed to maintain blinded conditions for the 
investigator’s team and the participants. The study data remained blinded until database lock and 
authorization of data release according to standard operating procedures. 
 
5.4 Study Assessments 
 
The following table provides the Schedule of Evaluations used in the study: 
 


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Study Period: Double-Blind 
Phase 
Dose Titration Period 
Stable Dosing Period 
Safety h 
Follow Up 
Study Visit 
Screening 
Visit 0 
Baseline 
Visit 1 
Week 2 
Visit 2 
Week 4 
Visit 3 
Week 6 
Visit 4 
Week 8 
Visit 5 
UNSHf 
Week 12 
Visit 6 
Week 
16g 
Visit 7
Week 20 
Visit 8 
Window (days): 
14 
+4 
+/-4 
+/-4 
+/-4 
+/-4 
 
+/-4 
+/-4 
+/-4 
Type of Contact: 
Office 
Office 
Office 
Office 
Office 
Office 
Office 
Office 
Office 
Office/Phone 
Call 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
 
 
Demographics, including smoking & 
alcohol history 
X 
 
 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
Prior/Concomitant therapy 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
X 
 
 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
 
X 
 
Hematology, serum chemistrya 
X 
 
 
 
 
X 
 
 
X 
 
Urine pregnancy test (women of 
childbearing potential) 
X 
X 
 
X 
 
X 
 
X 
X 
 
Hand x-rays for calcinosis (not 
required at Screening if performed in prior 
6  months) 
X 
 
 
 
 
 
 
 
 
 
Physician’s Global Assessment 
 
X 
 
 
 
 
 
 
X 
 
Patient’s Global Assessment 
 
X 
 
 
 
 
 
 
X 
 
PROMIS -29 
 
X 
 
 
 
 
 
 
X 
 
HAQ-DI/SHAQ 
 
X 
 
 
 
 
 
 
X 
 
HDISS-DU 
 
X 
 
 
 
 
 
 
X 
 
Raynaud’s phenomenon diary 
Xb 
Xc 
 
 
 
 
 
Xb 
Xc 
 
Digital Ulcer Assessment 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Digital photo of cardinal ulcer 
X 
 
 
 
 
 
 
 
X 
 
Dispense study medication 
 
X 
X 
X 
X 
X 
X 
X 
Xd 
 
Assess for Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Biomarkerse 
 
X 
 
 
 
 
 
 
X 
 


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a Participants with eGFR 15-29 ml/min or other laboratory abnormalities per physician judgment can repeat labs once during the screening period 
b Dispense 7-day diary; 
c Collect 7-day diary; 
d Open-Label study drug will be dispensed at this visit if participant is continuing to the OLE phase of the study. If a participant is exiting the study, all study drug should be 
returned at this visit and no more will be dispensed. 
e 10 mL for biomarkers: VEGF, tPA, sE-Selectin, BFGF, VCAM-1, ICAM 
f  This visit is for participants who experience toleration issues and return to clinic for assessment and dispense a lower dose. 
g Complete these visit assessment for any participants who terminate/withdrawal from the study prior to visit 7. 
h Complete this visit for any subject who does not enter the OLE. This can be a phone call if there are no new or ongoing adverse events attributable to the study medication  
and no digital ulcers to assess.  


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 
Given flexibility around subject and care provider scheduling, visits are not required to have 
occurred on a specific date, but rather within a defined window.    
 
Where analyses reference the timing of outcomes and/or covariates, the nominal visit or time 
point as collected in the database will be used.  For instances when there are scheduled visits 
and unscheduled visits in the same analysis time window, scheduled visits will be selected 
over unscheduled visits.  If there are multiple observations for scheduled visits within a 
window, the one closest to the visit target date will be utilized.  Where two observations are 
equi-distant from the target date the later will be utilized.   
 
Analysis Time Windows 
Period 
Visit  
Study Month (Day) 
Lower bound of 
Window (Day) 
Target Date (Day) and 
Per protocol window 
Upper bound of 
Window (Day) 
Screening 
Screening   
-14 
-14 to -1 
-1 
Dose Titration 
Baseline (0) 
0 
0 to 4 
7 
 
Week 2 (14) 
8 
14 + 4 
21 
 
Week 4 (28) 
22 
28 + 4 
35 
 
Week 6 (42) 
36 
42 + 4 
49 
 
Week 8 (56) 
50 
56 + 4 
70 
Stable Dosing 
Week 12 (84) 
71 
84 + 4 
98 
 
Week 16 (112) 
99 
112 + 4 
126 
Safety Follow-up 
Week 20 (140)* 
127 
448 + 10 
154 
*participants who enter into the open-label phase of the study did not have a week 20 visit; participant 
data from the open-label extension period are not included in the study. 
 
 
5.5 Imputation of Dates 
If partial dates occur, the convention for replacing missing dates for the purpose of calculating derived 
variables is as follows: 
 
For partial original baseline or historical condition dates (e.g., diagnosis): (a) if only the day is 
missing, and the month and year match the first dose date, then the day is assigned the first day of the 
month (01); otherwise the day assigned is 15; and (b) if both the day and month are missing then the 
day/month assigned is the first day of July (01JUL), as long as the date is before the first dose date; 
otherwise, the day/month assigned is the first day of January (01JAN). 
 
If start dates are entirely missing for adverse events or medications, then adverse events will be 
classified as treatment‐emergent and medications will be classified as concomitant. For partial AE or 
concomitant medication start dates or end dates, the table below describes the date imputation. 
 
 


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Missing  
Condition – 
START DATE 
Condition – 
END DATE 
Imputation 
Classification 
Start Day 
Start month & 
year match those 
of the first dose 
date 
End date > first 
dose date or 
ongoing 
Set start date = 
first dose date 
AE = treatment-emergent 
& med = concomitant 
End date < first 
dose date 
Set start date = 
01 
AE = not treatment 
emergent & med = prior 
Start year < first 
dose year 
End date > first 
dose date or 
ongoing 
Set start date = 
15 
AE = not treatment-
emergent & med = 
concomitant 
End date < first 
dose date 
Set start date = 
01 
AE = not treatment 
emergent & med = prior 
Start year = first 
dose year and 
start month < 
first dose month 
End date > first 
dose date or 
ongoing 
Set start date = 
15 
AE = not treatment-
emergent & med = 
concomitant 
End date < first 
dose date 
Set start date = 
01 
AE = not treatment 
emergent & med = prior 
Start year = first 
dose year and 
start month > 
first dose month 
All cases 
Set start date = 
15 
AE = treatment-emergent 
& med = concomitant 
Start Day & 
Start Month 
Start year 
matches first 
dose date 
End date > first 
dose date or 
ongoing 
Set start date = 
first dose date 
AE = treatment-emergent 
& med = concomitant 
End date < first 
dose date 
Set start date = 1 
and start month 
= end date 
month 
AE = not treatment 
emergent & med = prior 
Start year < first 
dose year 
All cases 
Set start date = 1 
and start month 
= JAN 
 
Start year > first 
dose year 
All cases 
Set start day =1 
and start month 
= JAN 
AE = treatment-emergent 
& med = concomitant 
End Day 
NA 
All 
Set end date = 
min(last day of 
month, day of 
visit date) 
NA 
End Day & 
End Month 
NA 
All 
Set end day =31 
and end month = 
DEC, or day and 
month of visit 
date if earlier 
NA 
 
 
6 Sample Size  
SSc is a rare disease. The planned sample size of 20 SSc participants is based on practical 
considerations to obtain preliminary estimates of the magnitude of treatment differences in efficacy 
and safety rather than a desired power for a pre-specified difference as would be necessary for a 


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confirmatory study. However, with this proposed sample of 20 participants (10 riociguat and 10 
placebo), we can calculate the magnitude of treatment differences (riociguat – placebo) for the 
primary efficacy endpoint – the change from baseline to end of double-blind treatment in digital ulcer 
net burden (a continuous endpoint), or safety outcomes – characterized by the proportion of 
participants who experience an AE.  There would be 80% power to detect an effect size (mean 
treatment difference divided by standard deviation) of 1.253 or greater with a two-sided type I error of 
5% in the primary endpoint, based on a two- sample t test.  Given the pilot nature of this Phase IIa 
study, the difference between mean change in digital ulcer net burden between riociguat and placebo 
that can be detected with sufficient power is large.  Similarly, we can calculate power for safety 
outcomes for this sample size:  there is 81% power to detect treatment differences of 51%, assuming 
40% of placebo-treated participants experience an AE based on a two-sample binomial test. 
 
7 General Analysis Considerations 
 
7.1 Timing of Analyses 
The final analysis of the double-blind period will be performed after all randomized participants have 
completed their 16-week visit or dropped out prior to their 16-week visit, all corresponding data have 
been entered, cleaned, locked and unblinded as per SABER SOPs. This SAP document was finalized 
and approved prior to the double-blind database lock and unblinding. 
 
7.2 Analysis Populations 
All randomized participants will be used in the analyses of subject disposition. 
 
7.2.1 
Modified Intention to Treat Population 
The main population for efficacy will be the modified intention-to-treat population (MITT), defined 
as all participants randomized, receiving at least one dose of treatment, and having at least one post-
baseline efficacy assessment. Participants will be analyzed by assigned treatment.   The primary 
endpoint and all secondary outcomes will be assessed using this analysis set.  Membership in the 
mITT analysis population was determined before study unblinding. 
 
7.2.2 
Per Protocol Population 
The Per Protocol population (PP) will consist of all participants in the MITT population who did not 
have a major protocol violation. Major protocol deviations are defined as eligibility criteria violations 
for which no exemption was granted, and study drug compliance <80% and >120%.   Membership in 
the PP analysis population will be determined before study unblinding.  Only the primary endpoint 
will be assessed using this analysis set (sensitivity analysis). 
 
7.2.3 
Safety Population 
The Safety Population is defined as all participants who were randomized and received at least one 
dose of the study drug. The Safety Population will be used for all safety analyses, as well as 
demographic and baseline analyses.  Participants will be analyzed by treatment received. If 
participants inadvertently receive both active drug and placebo, they will be included in the riociguat 
group.   
 
7.3 Covariates and Subgroups 
There are a limited number of covariates that will be incorporated in statistical models in our analyses 
because of the relatively small sample size in each treatment group:  the baseline outcome measure.  
We will not impute missing values for other baseline covariates in secondary and exploratory analyses 
in the mITT analysis set. 
 
No planned subgroup analysis will be performed using the primary end point.  
 
7.3.1 
Multi-center Studies 
Given that SSc is a relatively rare disease, many centers were required to obtain the required sample 


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size.  Study centers will not be incorporated as stratification into the analyses.   Descriptive statistics 
of the primary end point by treatment group, separately by center (Michigan [the largest enrolling 
site] and the remainder) will be provided.    
 
7.4 Missing Data 
We will summarize the extent of missing data over time for the primary end point.  We will 
investigate the missing data mechanism (missing at random, not missing at random), which is 
important for the validity of our analytic approaches, through exploratory analysis. Exploratory 
analyses will include plots of the mean profile of digital ulcer net burden at weeks 0, 2, 4, 6, 8, 12 and 
16 by treatment group for those who have complete data throughout the study and those who don’t, as 
well as plots of the mean change from baseline at weeks 2, 4, 6, 8, 12 and 16 in digital ulcer net 
burden in the two treatments within each group (completers and non-completers). If the plots reveal 
consistent differences between completers and non-completers within each of the treatment groups, 
then there is evidence that data are not missing at random. 
 
The primary analysis of the primary end point (see section 9.1) will use multiple imputation (which 
assumes a missing at random mechanism) to impute missing week 16 digital net ulcer burden values.  
The imputation model will include baseline digital ulcer net burden and all follow-up digital ulcer net 
burden values (allowing for the dependence of later time points on earlier time points), treatment 
group, and demographic variables (age and gender).  The analysis model will incorporate the 
uncertainty due to imputation in the calculation of the standard error, as described by Rubin.1  Pattern 
mixture models will be used in there is strong evidence that the data are not missing at random.2 
 
7.5 Interim Analyses and Data Monitoring 
No formal interim analyses were planned nor carried out for this study.  The study was overseen by a 
Data and Safety Monitoring Board (DSMB) that reviewed the pooled and by-treatment subject 
disposition, study conduct and safety data approximately every 6 months.   
 
7.6 Multiple Testing 
Two-sided p-values will be reported, and no adjustments for multiplicity will be made.  Given the rare 
nature of SSc and the consequent small sample size for this pilot Phase IIa study, the statistical power 
of any comparisons is limited (i.e., there is sufficient power to detect only large treatment 
differences). As such the analysis will be largely descriptive in nature as the study is not powered to 
determine a statistical difference between riociguat vs. placebo.  The p-values resulting from formal 
statistical tests will be interpreted from a hypothesis-generating, rather than a confirmatory 
framework. 
 
8  Summary of Study Data 
Descriptive summary statistics will be derived for all data at baseline, separately by treatment 
group and overall.  For efficacy, exploratory and safety data, data will be presented by treatment 
group.  Treatment group will be characterized as “Riociguat” and “Placebo”; for pooled 
summaries, “Overall” will be used as the column heading.  All tables will be annotated with the 
total population size relevant to that table/treatment, including any missing observations. 
 
For continuous variables, mean, standard deviation, median, interquartile range, minimum and 
maximum will be reported.  For categorical variables, number and percentages will be reported 
(excluding missing values).  Summaries will be provided by treatment group and overall.  Graphical 
methods will be heavily used in this pilot study to assess the pattern of response over time for key 
variables and to assess the relationships among variables.  
 
 
8.1 Subject Disposition 
The number of participants approached for study participation, the number consented and the number 
who did not consent (including reasons:  screen failures, refusals) will be summarized in a CONSORT 


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diagram.  The number of participants who dropped out prior to randomization, and the reasons for 
dropout, will be summarized.  The number randomized and treated and the number who dropped out 
in the dose titration period (baseline – week 8) and in the stable dosing period (week 8 – week 16) 
will be provided, as well as the number in each of the analysis populations (i.e., mITT, PP, Safety).  
Reasons for post-treatment dropout will be provided.    
 
8.2 Protocol Deviations 
Major protocol deviations that exclude a patient from the Per Protocol Population are described in 
section 7.2.2.  A listing of protocol deviations that exclude participants from the Per Protocol 
population will be provided. A listing of participants who receive exemptions for study eligibility will 
also be provided. 
 
8.3 Demographic and Baseline Variables 
Demographic variables include:  age at consent (defined as a continuous variable, e.g., 52.6 years), 
age by category (18 to 35 years, >35 to 55 years, >55 to 75 years, and >75 years), gender, race and 
ethnicity.  
 
Baseline is defined as pre-treatment measures, either at screening (if a measure was only assessed at 
screening) or at baseline (if a measure was assessed at baseline even if also assessed at screening).  
Baseline variables include:   
 
Number of active, indeterminate and total digital ulcers at baseline 
 
Disease duration since first non-Raynaud’s symptom at time of consent (years) 
 
Disease duration since Raynaud’s phenomenon at time of consent (years) 
 
Disease duration of scleroderma diagnosis at time of consent (years) 
 
Duration of digital ulcers at time of consent (years) 
 
SHAQ VAS finger ulcers interfere with daily activities 
 
Raynaud’s condition score 
 
Raynaud’s attacks/days  
 
Pain, numbness, and tingling during a RP attack 
 
Duration of attacks 
 
Patient assessment of RP 
 
Physician assessment of RP 
 
Creatinine (mg/dL), hemoglobin (g/dL), platelets (K/µl), WBC (K/ µl) (all at screening) 
 
8.4 Treatment Compliance 
Compliance with study medication (tablets) will be calculated, for each participant, as the proportion 
of time (weeks) that a participant took the full or partial contents of the syringe.  Specifically, the 
percent compliance is calculated as 100 x the ratio of the number of weeks during the double-blind 
period when the participant took the tablets divided by the number of weeks during the double-blind 
period during which the participant was expected to take study medication. Participants were expected 
to take study medication unless it was temporarily discontinued due to an AE or permanently 
discontinued.  The study medication log (Form 027), adverse event form (Form 044), serious adverse 
event form (Form 045) and final status form (Form 035) are used to derive the compliance measure. 
 
The summary statistics will be produced in accordance with section 9. 
 
9 Efficacy Analyses 
 
9.1  Primary Efficacy Analysis 
The primary endpoint is the mean change from baseline to end of the double-blind study treatment 
phase (Week 16) in the digital ulcer net burden. For the primary analysis, changes in digital ulcer net 
burden will be compared in the two treatment groups using an ANCOVA model with terms for 
treatment group and baseline digital ulcer net burden value. If the assumptions of this parametric 


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model are not met, an alternative non-parametric model will be used. This model is based on the 
extension of the Wilcoxon rank-sum test to allow for covariate adjustment. This rank ANCOVA can 
provide additional power associated with baseline covariate adjustment, even when the outcome 
variable is not normally distributed. 
 
Predicted mean change from baseline to week 16 for an exemplary participant by treatment group will 
be provided, as well as the estimate of the treatment effect at week 16, adjusted for baseline 
covariates, and corresponding 95% confidence interval and p-value for the treatment effect.   
 
9.2  Secondary Efficacy Analyses 
 
9.2.1 
Secondary Analyses of Primary Efficacy End point 
Several sensitivity analyses will be performed to assess how alternative approaches to missing data 
and model assumptions affect the conclusions of the analysis of the primary outcome: 
 
 
Analysis of the primary efficacy variable as described above will also be performed on the PP 
Population.   
 
9.2.2 
Analyses of Secondary End points 
Analysis for secondary outcome measures that are continuous will be performed using a similar 
approach as that for the primary endpoint. We will compare the change in each secondary outcome 
measure from baseline to week 16 between the two treatment groups using an ANCOVA model or its 
non-parametric counterpart if the model assumptions aren’t met.  Analyses of secondary outcomes 
measures that are discrete will be performed using Fisher’s exact tests. Analyses of secondary 
outcome measure that are counts will be performed using Poisson regression.  Analyses of time-to-
event secondary outcome measures will be performed using log-rank tests and summarized using 
Kaplan-Meier survival plots. 
 
10 Safety Analyses 
Safety data, including AEs, clinical laboratory tests, vital signs, physical examinations, and 
concomitant medication usage will be summarized descriptively by treatment group for the Safety 
Population; select parameters will also be summarized for the entire population (overall).  
 
10.1 Adverse Events 
Descriptive summary statistics for treatment-emergent adverse events (AEs) will be reported.  The 
number of treatment-emergent AEs and the frequencies (number and percentage) of participants with 
one or more treatment-emergent AE will be summarized by treatment group, overall, by severity, and 
by body system.  Coding of adverse events into body system was performed by the study chair for 
adverse events and by the medical monitors for serious adverse events.  All treatment-emergent AEs 
related to study drug will be summarized, as will the frequencies of participants with one or more 
treatment-emergent AE related to study drug.  Similarly, all treatment-emergent AEs causing study 
discontinuation, and frequencies of participants experience these, will be summarized. 
 
AEs and SAEs of special interest include: 
 
Symptomatic hypotension 
 
Serious hemoptysis 
A listing of these AEs will be presented. 
 
A subject listing of all treatment-emergent AEs and treatment-emergent AEs causing study 
discontinuation will be presented.   
In accordance with clincaltrial.gov reporting requirements, the following table summarizing adverse 
events is required and will be provided: 


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● Other (Not Including Serious) Adverse Events: A table of anticipated and unanticipated 
events (not included in the serious adverse event table) that exceed 5% within either treatment 
group, grouped by organ system, with number and frequency of such events in each treatment 
group. 
 
Adverse events that occurred after consent and before treatment will be listed. 
 
10.2 Deaths, Serious Adverse Events and other Significant Adverse Events 
Descriptive summary statistics for treatment-emergent serious adverse events (SAEs) will be reported.  
The number of treatment-emergent SAEs and the frequencies (number and percentage) of participants 
with one or more treatment-emergent SAE will be summarized by treatment group, overall and by 
body system.  Coding into body system was performed by the medical monitors for SAEs.  All 
treatment-emergent SAEs related to study drug will be summarized, as will the frequencies of 
participants with one or more treatment-emergent SAE related to study drug.  Similarly, all treatment-
emergent SAEs causing study discontinuation, and frequency of participants experiencing these, will 
be summarized.  
 
A subject listing of all treatment emergent SAEs, SAEs causing study discontinuation, and deaths 
(including the post-treatment follow-up period through month 12) will be presented. 
 
In accordance with clincaltrial.gov reporting requirements, the tables below summarizing deaths and 
SAEs are required: 
● All-Cause Mortality:   A table of all anticipated and unanticipated deaths due to any cause, 
with number and frequency of such events in each treatment group. 
● Serious Adverse Events: A table of all anticipated and unanticipated serious adverse events, 
grouped by organ system, with number and frequency of such events in each treatment group. 
 
10.3 Pregnancies 
A listing of all pregnancies occurring after the start of study medication will be provided.  
 
10.4 Clinical Laboratory Evaluations 
The safety evaluation of laboratory data will include: 
 
 
Incidence rates of treatment-emergent laboratory values outside of normal range. 
 
Descriptive analysis of continuous laboratory parameters, and their changes from baseline by 
treatment group and visit. 
 
Descriptive analysis of vital signs, and their changes from baseline, will be performed by treatment 
group and visit.   
 
For ECGs, the status pre-treatment and post-treatment will be tabulated.  The incidence rates of 
treatment-emergent ECG abnormalities will be tabulated by treatment group.  A descriptive analysis 
of continuous ECG parameters and their changes from baseline by treatment group and visit will also 
be presented. 
 
10.5  Extent of Exposure 
The following outcomes will be summarized descriptively by treatment group: 
 
Duration of treatment: Treatment duration (in days) is calculated as the stop date of 
treatment – start date of treatment + 1. Treatment interruptions are ignored. 
 
Extent of exposure: Exposure (in mg) is calculated for each participant by adding the daily 
dose (TID dosing is prescribed) over the duration of treatment. 


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 
Cumulative treatment exposure:  The number of participants treated at least 1 day, 8 weeks 
(through the dose titration period) and 16 weeks (through the stable dosing period) will be 
calculated and summarized. 
 
Study treatment dose titration by visit: The number of participants at each dose for each 
visit will be summarized.   
 
Study treatment dose titration: The number of participants for each dosing pattern (across 
visits in the dose titration and stable dosing periods) by visit will be summarized. 
 
10.6 Prior and Concurrent Medications  
 
The proportion of participants on immunosuppressive therapies, vasodilators, and PDE-5 inhibitors 
prior to the start of study medication will be summarized in the baseline table by treatment group and 
overall, using summary statistics in accordance with section 9. 
 
No medication coding dictionary was used in this study.  The investigators characterized concomitant 
medications by name. 
 
10.7  Other Safety Measures 
Vital signs (systolic and diastolic blood pressure) will be summarized using descriptive statistics by 
clinical visit (through week 16) and treatment group, as both observed value at the time point of 
interest and the change from baseline values. 
 
11  Reporting Conventions 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. The mean, standard deviation, and any other statistics other than quantiles, will be 
reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data. 
Estimated parameters, not on the same scale as raw observations (e.g., regression coefficients) 
will be reported to 3 significant figures.  
 
12 Summary of Changes to the Protocol and/or SAP 
The changes from the protocol-specified definitions of aims, outcomes and statistical analytic 
approaches are outlined below.  These changes reflect advances in our knowledge of digital ulcers and 
scleroderma since the design of the study in 2014-2015 that were not incorporated as protocol 
amendments, but were discussed during the formation of the Statistical Analysis Plan.  These changes 
are documented herein and represent changes made prior to the database lock. 
 
1. Additional Secondary End points 
New information from FDA regulators expands the consideration of other digital ulcer end points 
described below.  In addition, an additional measure of hand function has been added, based on 
categories of the HAQ-DI that are associated with hand function.  
 
PROTOCOL: 
N/A 
 
SAP: 
Section  4.2.2 Secondary Efficacy End points  
 
Proportion of participants with healing of all DUs at baseline by week 16.  Baseline DUs are 
considered healed when classified as ‘healed’ and not ‘active’ or ‘indeterminate’ by week 16.  
All baseline ulcers must be healed for the participant to be classified as having all baseline 
ulcers healed.  Note that this end point does not consider whether a participant develops new 
DUs during the course of the study. 
 
Proportion of participants with no DUs at week 16.  This end point does not consider the 


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number of ulcers at baseline or during the course of the study; only the absence of ‘active’ and 
‘indeterminate’ DUs at week 16.   
 
Change from baseline to Week 16 in the composite score for hand function.  The sum of the 
individual scores for dressing, hygiene, and grip from the HAQ-DI will be calculated.  These 
categories are associated with hand function.   
 
2.  Reporting of Laboratory Data Abnormalities 
The reporting of the incidence of pre-specified laboratory data abnormalities was noted in the protocol; 
however, there no specific laboratory data abnormalities were defined and standard reporting of 
laboratory abnormalities that are adverse events are reported. 
 
PROTOCOL: 
Section 8.3.3. Safety 
The safety evaluation of laboratory data will include: 
 
Incidence rates of pre-specified laboratory data abnormalities. 
 
SAP: 
None 
 
15 
 References 
 
1.  Rubin DB. Multiple imputation for nonresponse in surveys: John Wiley & Sons; 2004. 
2.  Little RJ, Wang Y. Pattern-mixture models for multivariate incomplete data with covariates. 
Biometrics. 1996;52(1):98-111. Epub 1996/03/01. PubMed PMID: 8934587. 
 
16 Listing of Tables, Listings and Figures 
A separate document provides the mock tables, listings and figures.