Riociguat in Scleroderma Associated Digital Ulcers

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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).

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).

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).

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).

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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