Trial Outcomes & Findings for Riociguat in Scleroderma Associated Digital Ulcers (NCT NCT02915835)

NCT ID: NCT02915835

Last Updated: 2019-09-24

Results Overview

Digital ulcer net burden is defined as the total number of "active" and indeterminate digital ulcers at an assessment. Active ulcers are defined as having a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity. A healed ulcer has complete re-epithelialization.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 17 participants
• Primary outcome timeframe: Baseline to Week 16
• Results posted on: 2019-09-24

Participant Flow

Participant milestones

Measure	Riociguat 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) Riociguat: 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)	Placebo 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Overall Study STARTED	9	8
Overall Study COMPLETED	8	7
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Measure	Riociguat 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) Riociguat: 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)	Placebo 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Overall Study Physician Decision	1	0
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Riociguat in Scleroderma Associated Digital Ulcers

Baseline characteristics by cohort

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;	Total n=17 Participants Total of all reporting groups
Age, Continuous	43 years STANDARD_DEVIATION 14 • n=5 Participants	61 years STANDARD_DEVIATION 17 • n=7 Participants	51 years STANDARD_DEVIATION 18 • n=5 Participants
Age, Customized Age Categories · 18 to 35 years	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Age, Customized Age Categories · >35 to 55 years	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Age, Customized Age Categories · >55 to 75 years	2 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants
Age, Customized Age Categories · >75 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants n=5 Participants	8 Participants n=7 Participants	17 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Number of digital ulcers at screening	2.67 number of digital ulcers STANDARD_DEVIATION 1.803 • n=5 Participants	2.50 number of digital ulcers STANDARD_DEVIATION 1.690 • n=7 Participants	2.59 number of digital ulcers STANDARD_DEVIATION 1.698 • n=5 Participants
Type of scleroderma at screening limited cutaneous	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Type of scleroderma at screening diffuse cutaneous	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants
Time since first non-Raynaud's Symptom	7.09 years STANDARD_DEVIATION 5.933 • n=5 Participants	17.49 years STANDARD_DEVIATION 11.09 • n=7 Participants	11.98 years STANDARD_DEVIATION 10.060 • n=5 Participants
Time since first Raynaud's Phenomenon symptom	7.49 years STANDARD_DEVIATION 6.649 • n=5 Participants	14.5 years STANDARD_DEVIATION 7.872 • n=7 Participants	11.01 years STANDARD_DEVIATION 7.920 • n=5 Participants
Time since Scleroderma Diagnosis	6.23 years STANDARD_DEVIATION 5.765 • n=5 Participants	15.0 years STANDARD_DEVIATION 8.05 • n=7 Participants	10.37 years STANDARD_DEVIATION 8.156 • n=5 Participants
Time since first Digital Ulcer	5.41 years STANDARD_DEVIATION 4.563 • n=5 Participants	8.07 years STANDARD_DEVIATION 6.842 • n=7 Participants	6.66 years STANDARD_DEVIATION 5.725 • n=5 Participants
SHAQ: Finger ulcers interfere with daily activities in past week	116 units on a scale n=5 Participants	55 units on a scale n=7 Participants	98 units on a scale n=5 Participants
Raynaud's condition score	3.4 units on a scale STANDARD_DEVIATION 2.2 • n=5 Participants	5.4 units on a scale STANDARD_DEVIATION 1.6 • n=7 Participants	4.5 units on a scale STANDARD_DEVIATION 2.1 • n=5 Participants
Number of Raynaud's attacks per day	4.3 attacks per day STANDARD_DEVIATION 1.7 • n=5 Participants	2.2 attacks per day STANDARD_DEVIATION 1.7 • n=7 Participants	3.3 attacks per day STANDARD_DEVIATION 2.0 • n=5 Participants
Pain during a Raynaud's attack	54.9 units on a scale STANDARD_DEVIATION 13.1 • n=5 Participants	37.2 units on a scale STANDARD_DEVIATION 24.6 • n=7 Participants	46.6 units on a scale STANDARD_DEVIATION 20.7 • n=5 Participants
Numbness during a Raynaud's attack	40.5 units on a scale STANDARD_DEVIATION 15.9 • n=5 Participants	32.0 units on a scale STANDARD_DEVIATION 30.2 • n=7 Participants	36.5 units on a scale STANDARD_DEVIATION 23.2 • n=5 Participants
Tingling during a Raynaud's attack	34.8 units on a scale STANDARD_DEVIATION 16.6 • n=5 Participants	26.9 units on a scale STANDARD_DEVIATION 16.1 • n=7 Participants	31.1 units on a scale STANDARD_DEVIATION 16.3 • n=5 Participants
Duration of Raynaud's attacks	101.4 minutes STANDARD_DEVIATION 117.3 • n=5 Participants	47.9 minutes STANDARD_DEVIATION 51.6 • n=7 Participants	76.4 minutes STANDARD_DEVIATION 93.8 • n=5 Participants
Severity of patient assessment of Raynaud's phenomenon	7.1 units on a scale STANDARD_DEVIATION 1.4 • n=5 Participants	4.2 units on a scale STANDARD_DEVIATION 2.7 • n=7 Participants	5.8 units on a scale STANDARD_DEVIATION 2.5 • n=5 Participants
Severity of patient assessment of digital ulcers	8.0 units on a scale STANDARD_DEVIATION 1.5 • n=5 Participants	6.7 units on a scale STANDARD_DEVIATION 1.9 • n=7 Participants	7.4 units on a scale STANDARD_DEVIATION 1.8 • n=5 Participants
Severity of physician assessment of Raynaud's phenomenon	6.1 units on a scale STANDARD_DEVIATION 1.0 • n=5 Participants	5.4 units on a scale STANDARD_DEVIATION 3.0 • n=7 Participants	5.8 units on a scale STANDARD_DEVIATION 2.1 • n=5 Participants
Severity of physician assessment of digital ulcers	6.4 units on a scale STANDARD_DEVIATION 1.9 • n=5 Participants	6.3 units on a scale STANDARD_DEVIATION 2.6 • n=7 Participants	6.4 units on a scale STANDARD_DEVIATION 2.1 • n=5 Participants
Systemic scleroderma-related antibodies Anti-centromere B	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Systemic scleroderma-related antibodies Anti-topoisomerase I	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Systemic scleroderma-related antibodies Anti-RNA polymerase III	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Systemic scleroderma-related antibodies Not done	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Baseline use of vasodilators	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Digital ulcer net burden is defined as the total number of "active" and indeterminate digital ulcers at an assessment. Active ulcers are defined as having a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity. A healed ulcer has complete re-epithelialization.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to End of Double-blind Treatment (Week 16) in Digital Ulcer Net Burden	-1.22 ulcers Standard Error 0.458	-0.98 ulcers Standard Error 0.425

SECONDARY outcome

Timeframe: Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participant whose active digital ulcer that was identified and designated by the investigator as the cardinal ulcer at Baseline is healed by week 16. The cardinal ulcer will be selected by the investigator based on the clinical judgment that it was amenable to and evaluable for healing. If there are several active digital ulcers, the cardinal ulcer could be either the largest or the most painful ulcer, or the ulcer that disturbed the patient the most. Active ulcers are defined as having a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants With Healing of Their Cardinal DU by Week 16	4 Participants	6 Participants

SECONDARY outcome

Timeframe: Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants whose baseline DUs are considered healed (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. Active ulcers are defined as having a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity. A healed ulcer has complete re-epithelialization.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants With Healing of All DUs at Baseline by Week 16	3 Participants	3 Participants

SECONDARY outcome

Timeframe: Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants with no digital ulcers 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. Active ulcers are defined as having a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity. A healed ulcer has complete re-epithelialization.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants With no DUs at Week 16	2 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants with new (i.e., not present at baseline) active and indeterminant DUs from baseline to Week 16. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants With New Active and Indeterminate DU(s) Over the Course of the Double-blind Period	3 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants who develop a DIP pressure ulcer at baseline to Week 16. Pressure ulcer is defined as an active or indeterminate ulcer. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants Who Develop Pressure Ulcers at Distal Interphalangeal (DIP) Location Over the Course of the Double-blind Period.	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants who develop a PIP pressure ulcer at baseline to Week 16. Pressure ulcer is defined as an active or indeterminate ulcer. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants Who Develop Pressure Ulcers at Proximal Interphalangeal (PIP) Location Over the Course of the Double-blind Period.	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants who develop a MCP pressure ulcer at baseline to Week 16. Pressure ulcer is defined as an active or indeterminate ulcer. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants Who Develop Pressure Ulcers at Metacarpophalangeal (MCPs) Location Over the Course of the Double-blind Period.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants who develop a pressure ulcer at at the elbows at baseline to Week 16. Pressure ulcer is defined as an active or indeterminate ulcer. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants Who Develop Pressure Ulcers at the Elbows Over the Course of the Double-blind Period.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants whose DIP pressure ulcers during the double-blind period were healed at Week 16. Pressure ulcer is defined as an active or indeterminate ulcer. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants With Healing of All Pressure Ulcers at the Distal Interphalangeal (DIP) Over the Course of the Double-blind Period.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants whose PIP pressure ulcers during the double-blind period were healed at Week 16. Pressure ulcer is defined as an active or indeterminate ulcer. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants With Healing of All Pressure Ulcers at the Proximal Interphalangeal (PIP) Over the Course of the Double-blind Period.	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants whose MCP pressure ulcers during the double-blind period were healed at Week 16. Pressure ulcer is defined as an active or indeterminate ulcer. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants With Healing of All Pressure Ulcers at the Metacarpophalangeal (MCPs) Over the Course of the Double-blind Period.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants whose pressure ulcers at the elbows during the double-blind period were healed at Week 16. Pressure ulcer is defined as an active or indeterminate ulcer. An active ulcer is defined as a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity.

Outcome measures

Measure	Riociguat n=8 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants With Healing of All Pressure Ulcers at the Elbows Over the Course of the Double-blind Period.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

This is 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. One active digital ulcer must be identified and designated by the investigator as the cardinal ulcer at Baseline. 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. Active ulcers are defined as having a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. Week 16 is defined as the end of the double-blind period; however, the protocol allowed a visit window of +/- 4 weeks.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Time to Healing of Cardinal DU	16.57 weeks Interval 2.0 to 17.57	16.07 weeks Interval 16.0 to 16.14

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

This is 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. A healed ulcer has complete re-epithelialization. Week 16 is defined as the end of the double-blind period; however, the protocol allowed a visit window of +/- 4 weeks.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Time to Healing of All Baseline DU	16.00 weeks Interval 2.0 to 16.86	16.00 weeks Interval 14.86 to 16.43

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

This is 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. Active ulcers are defined as having a denuded area with defined border and loss of epithelialization, loss of epidermis and dermis. An indeterminate ulcer is defined as denudation that could not be visualized and no other clinical features of activity. A healed ulcer has complete re-epithelialization. Week 16 is defined as the end of the double-blind period; however, the protocol allowed a visit window of +/- 4 weeks.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Time to Development of New ('Active' or 'Indeterminate') DU	16.00 weeks Interval 15.71 to 16.86	15.86 weeks Interval 15.57 to 16.43

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

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. A score of 0 indicates no difficulty and 10 indicates extreme difficulty with Raynaud's condition. A higher score means a worse outcome. The mean score will be calculated across the 7-day screening and week 16 periods for each participant.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Raynaud's Condition Score	-1.15 units on a scale Standard Error .691	-0.82 units on a scale Standard Error .691

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

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.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Number of Raynaud's Attacks/Day	-1.24 attacks per day Standard Error .323	-0.96 attacks per day Standard Error .323

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The mean duration of attacks (in minutes) 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.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Duration of Raynaud's Attacks	-44.81 minutes Standard Error 15.846	150.3 minutes Standard Error 15.846

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Pain because of Raynaud's disease (characterized as pain during a Raynaud's attack) is defined on a visual analogue scale, where 0 indicates no pain and 100 indicates very severe pain. A higher score means a worse outcome. The mean of the scales over a 7-day period are reported. 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.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Patient's Assessment of Pain During a Raynaud's Attack	-0.30 units on a scale Standard Error 6.600	-7.01 units on a scale Standard Error 6.600

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Numbness because of Raynaud's disease (characterized as numbness during a Raynaud's attack) is defined on a visual analogue scale, where 0 indicates no numbness and 100 indicates very severe numbness. A higher score means a worse outcome. The mean of the scales over a 7-day period are reported. 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.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Patient's Assessment of Numbness During a Raynaud's Attack	-19.73 units on a scale Standard Error 8.899	-15.44 units on a scale Standard Error 8.899

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Tingling because of Raynaud's disease (characterized as tingling during a Raynaud's attack) is defined on a visual analogue scale, where 0 indicates no tingling and 100 indicates very severe tingling. A higher score means a worse outcome. The mean of the scales over a 7-day period are reported. 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.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Patient's Assessment of Tingling During a Raynaud's Attack	1.18 units on a scale Standard Error 7.118	-7.49 units on a scale Standard Error 7.118

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The severity of Raynaud's phenomenon, as assessed by the physician, ranges from 0 (not at all severe) to 10 (extremely severe). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Physician's Assessment of Severity of Raynaud's Disease	-3.00 units on a scale Standard Error 0.736	-1.86 units on a scale Standard Error 0.788

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The severity of digital ulcers, as assessed by the physician, ranges from 0 (not at all severe) to 10 (extremely severe). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Physician's Assessment of Severity of Digital Ulcers	-3.54 units on a scale Standard Error 0.886	-3.81 units on a scale Standard Error 0.948

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Severity of Raynaud's disease is calculated as the mean response on a 0-10 Likert scale.

The severity of Raynaud's phenomenon, as assessed by the patient, ranges from 0 (not at all severe) to 10 (extremely severe). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Patient's Assessment of Severity of Raynaud's Disease	-3.47 units on a scale Standard Error 0.764	-1.41 units on a scale Standard Error 0.764

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Severity of digital ulcer(s) is calculated as the mean response on a 0-10 Likert scale.

The severity of digital ulcers, as assessed by the patient, ranges from 0 (not at all severe) to 10 (extremely severe). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Patient's Assessment of Severity of Digital Ulcers	-4.63 units on a scale Standard Error 0.935	-4.00 units on a scale Standard Error 0.935

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

This assessment represents the patient's assessment of the patient's global scleroderma on a 0 (excellent) -10 (extremely poor) Likert scale. A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Patient's Global Assessment for Overall Disease.	0.31 units on a scale Standard Error 0.915	-1.19 units on a scale Standard Error 0.915

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

This assessment represents the physician's assessment of the patient's current disease activity on a 0 (excellent) -10 (extremely poor) Likert scale. A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Physician's Global Assessment for Overall Disease.	-1.17 units on a scale Standard Error 0.548	-0.66 units on a scale Standard Error 0.586

SECONDARY outcome

Timeframe: Baseline/Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the physical function domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., better outcome).

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in PROMIS-29 Physical Function	-2.46 t-score Standard Error 1.27	-2.24 t-score Standard Error 1.227

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the anxiety domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).y.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in PROMIS-29 Anxiety	-3.11 t-score Standard Error 2.578	-1.50 t-score Standard Error 2.578

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the depression domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in PROMIS-29 Depression	-3.35 t-score Standard Error 1.731	-0.25 t-score Standard Error 1.731

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the fatigue domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in PROMIS-29 Fatigue	0.64 t-score Standard Error 1.903	0.46 t-score Standard Error 1.903

SECONDARY outcome

Timeframe: Baseline/Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the sleep disturbance domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e.,worse outcome).

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in PROMIS-29 Sleep Disturbance	-0.47 t-score Standard Error 1.091	0.94 t-score Standard Error 1.091

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the pain interference domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in PROMIS-29 Pain Interference	-3.69 t-score Standard Error 1.798	-3.06 t-score Standard Error 1.798

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the ability to participate in social roles and activities domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., better outcome).

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in PROMIS-29 Ability to Participate in Social Roles and Activities	-1.68 t-score Standard Error 1.104	-0.46 t-score Standard Error 1.104

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the pain intensity domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in PROMIS-29 Pain Intensity	-2.74 t-score Standard Error 0.702	-1.63 t-score Standard Error 0.702

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI overall score ranges from 0 (no disability) to 3 (severe disability). Higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Overall HAQ-DI Score	-0.01 score on a scale Standard Error 0.149	-0.06 score on a scale Standard Error 0.160

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Dressing and Grooming	-0.16 score on a scale Standard Error 0.18	0.05 score on a scale Standard Error 0.236

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Hygiene	-0.39 score on a scale Standard Error 0.279	-0.27 score on a scale Standard Error 0.298

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Arising	0.36 score on a scale Standard Error 0.235	0.02 score on a scale Standard Error 0.251

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Reach	0.37 score on a scale Standard Error 0.253	0.01 score on a scale Standard Error 0.271

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Eating	-0.53 score on a scale Standard Error 0.154	0.03 score on a scale Standard Error 0.166

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Grip	0.16 score on a scale Standard Error 0.215	-0.18 score on a scale Standard Error 0.230

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Walking	0.35 score on a scale Standard Error 0.199	-0.12 score on a scale Standard Error 0.214

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Common Daily Activities (IADL).	-0.29 score on a scale Standard Error 0.260	0.04 score on a scale Standard Error 0.278

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability).The sum of the individual scores for dressing, hygiene, and grip from the HAQ-DI defines the composite score for hand function. The HAQ-DI composite score for hand function ranges from 0 (no disability) to 9 (severe disability). A higher score means worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in HAQ-DI Composite Score for Hand Function	-0.47 score on a scale Standard Error 0.492	-0.32 score on a scale Standard Error 0.527

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) questionnaire is a 24-item PRO measure. Each item is 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). The total HDISS-DU score is the mean of valid items, ranging from 1 to 6. Higher scores represent increased disability in hand functioning.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Total Hand Disability in Systemic Sclerosis-DU (HDISS-DU) Score	-0.47 score on a scale Standard Error 0.492	-0.32 score on a scale Standard Error 0.527

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much finger ulcers interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Burden of Digital Ulcers	-43.09 score on a scale Standard Error 18.457	-53.47 score on a scale Standard Error 20.159

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much Raynaud's interfered with daily activities ranges from 0 (does not limit activities) to 150 (very severe limitation). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Raynaud's Disease	-23.78 score on a scale Standard Error 15.6	-25.40 score on a scale Standard Error 16.982

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment

Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much intestinal problems interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Gastrointestinal Involvement	16.72 score on a scale Standard Error 13.787	-7.39 score on a scale Standard Error 14.975

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much breathing problems interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Breathing	8.35 score on a scale Standard Error 8.90	-12.69 score on a scale Standard Error 8.978

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for disease severity ranges from 0 (no disease) to 150 (very severe). A higher score means a worse outcome.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Overall Disease,	-50.35 score on a scale Standard Error 9.039	-35.74 score on a scale Standard Error 9.751

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants who experience digital ischemia requiring intravenous prostacyclin or digital gangrene or amputation during the double-blind period of the trial. These outcomes are collected within Adverse Events

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants Who Experience Digital Ischemia Requiring Intravenous Prostacyclin or Digital Gangrene or Amputation During the Trial.	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

The proportion of participants who developed osteomyelitis during the double-blind period of the trial. Osteomyelitis is collected as an Adverse Event.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Proportion of Participants Who Develop Osteomyelitis During The Trial	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma	-29.8 pg/ml Standard Error 9.5	-34.7 pg/ml Standard Error 10.1

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma	-1.2 ng/ml Standard Error 0.5	-0.5 ng/ml Standard Error 0.5

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma	-4.7 ng/ml Standard Error 1.9	-2.5 ng/ml Standard Error 2.0

SECONDARY outcome

Timeframe: Baseline and Week 16

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma	0.20 pg/ml Standard Error 0.28	-0.03 pg/ml Standard Error 0.29

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma	10.3 ng/ml Standard Error 10.4	-3.4 ng/ml Standard Error 11.0

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Modified Intent to Treat Population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment.

Outcome measures

Measure	Riociguat n=9 Participants 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) Riociguat: 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)	Placebo n=8 Participants 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma	70.5 ng/ml Standard Error 47.3	-39. ng/ml Standard Error 50.2

Adverse Events

Riociguat

Serious events: 3 serious events

Other events: 9 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Measure	Riociguat n=9 participants at risk 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) Riociguat: 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)	Placebo n=8 participants at risk 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Blood and lymphatic system disorders Lymphoma	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Cardiac disorders NSTEMI	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Vascular disorders Digital ischemia of the right third toe	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Vascular disorders Right 4th digit ulcer	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.

Other adverse events

Measure	Riociguat n=9 participants at risk 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) Riociguat: 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)	Placebo n=8 participants at risk 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. Placebo: Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Musculoskeletal and connective tissue disorders Left Shoulder rotator cuff tear	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Musculoskeletal and connective tissue disorders Left elbow bursitis	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Blood and lymphatic system disorders Anemia	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Blood and lymphatic system disorders Splenic infarct	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Cardiac disorders Heart Murmur	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Cardiac disorders Left bundle bramch block on EKG	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Gastrointestinal disorders Diarrhea	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Gastrointestinal disorders GERD	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Gastrointestinal disorders Nausea	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
General disorders Hot flashes	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Hepatobiliary disorders Elevated liver enzymes	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Infections and infestations Right calf infection	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Infections and infestations Ulcer infection	22.2% 2/9 • Number of events 2 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Injury, poisoning and procedural complications Right arm laceration	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Musculoskeletal and connective tissue disorders Calcinosis Ulcer over Right Knee	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Musculoskeletal and connective tissue disorders Left Shoulder Pain	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Nervous system disorders Headache	33.3% 3/9 • Number of events 3 • 16 weeks 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.	37.5% 3/8 • Number of events 3 • 16 weeks 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.
Nervous system disorders Lightheadednes	22.2% 2/9 • Number of events 2 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Surgical and medical procedures Shoulder surgery	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Vascular disorders Cyanosis	0.00% 0/9 • 16 weeks 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.	12.5% 1/8 • Number of events 1 • 16 weeks 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.
Vascular disorders Worsening Raynaud's	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.
Vascular disorders Worsening digital ulcer	11.1% 1/9 • Number of events 1 • 16 weeks 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.	0.00% 0/8 • 16 weeks 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.

Additional Information

Dr. Cathie Spino

University of Michigan

Phone: 7346155469

Email: spino@umich.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place