Scleroderma, Digital Ulcers
Conditions
Keywords
Scleroderma, Digital Ulcer
Brief summary
The primary objective of this study is to provide preliminary data on the efficacy (digital ulcer net burden) and safety of riociguat administered 3 times daily (TID) in comparison to placebo in patients with scleroderma-associated digital ulcers
Detailed description
This clinical trial is a US, multicenter, double-blind, randomized placebo-controlled, parallel- group study with a total of 20 participants planned to be randomized (approximately 10 participants to the riociguat group and 10 to the placebo group). In addition, a standardized wound care protocol will be followed by the investigators and digital photography will be taken of the cardinal ulcer. The study will allow standard of care medications for the management of DU as background therapy. These may include calcium channel blockers, low dose aspirin, angiotensin enzyme inhibitors, etc. and will be determined by the participant's local physician. The study design consists of three phases: * Screening phase: up to 2 weeks * Double-blind Treatment phase: 16 weeks of double-blind treatment, consisting of: * Dose titration period of up to 8 weeks, and * Stable dosing period of up to 8 weeks * Open-label Extension phase for participants with active DU at the end of the double- blind treatment phase or development of an active DU within a month of completing double-blind phase, consisting of: * Dose titration phase of up to 8 weeks * Stable dosing period for 8 weeks
Interventions
DRUGRiociguat
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)
DRUGPlacebo
Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Sponsors
Bayer
Dinesh Khanna, MD, MS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed written informed consent 2. Men or women aged 18 years and older 3. Diagnosis of Systemic sclerosis, as defined by 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc 4. Patients had to have at least one visible, active ischemic DU at baseline located at or distal to the proximal interphalangeal joint, and that developed or worsened within 8 weeks prior to screening. NOTE: Presence of eschar will not be considered an active ulcer 5. Females of reproductive potential (FRP) must have a negative, pre-treatment urine pregnancy test. 6. FRP must obtain monthly urine pregnancy tests during treatment and one month after treatment discontinuation. Post-menopausal women (defined as no menses for at least 1 year or post-surgical from bilateral oophorectomy) are not required to undergo a pregnancy test. 7. FRP and all non-vasectomized male participants must agree to use reliable contraception when sexually active. (For FRP's, 'Adequate contraception' is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g., condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). This applies from the time of signing the informed consent form until one month after the last study drug administration.) 8. Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent), nonsteroidal anti- inflammatory drugs (NSAIDs), angiotensin receptor blockers, angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers are permitted if the participant is on a stable dose for ≥ 2 weeks prior to and including the baseline visit 9. Ability to comply with the clinical visits schedule and the study-related procedures.
Exclusion criteria
1. Active DU related to calcinosis (as assessed by clinical examination or radiographic evaluation at screening) 2. Medical and surgical history * Major surgery (including joint surgery) within 8 weeks prior to screening * Participants with a history of malignancy in the last 5 years other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ 3. Hepatic-related criteria \- Hepatic insufficiency classified as Child-Pugh C at screening (see Appendix 11.1 for classification table) at screening visit 4. Renal-related criteria * Estimated glomerular filtration rate (eGFR) \< 15 mL/min/1.73m2 (MDRD formula) or on dialysis at the screening visit * Cardiovascular-related criteria * Sitting systolic blood pressure \< 95 mmHg at the screening visit * Sitting heart rate \< 50 beats per minute (BPM) at the screening visit * Left ventricular ejection fraction \< 40% prior to screening on echocardiogram done as part of clinical care 5. Pulmonary-related criteria * Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization * Any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening. Massive hemoptysis being defined as acute bleeding \>240 mL in a 24-hour period or recurrent bleeding \>100 mL/d over several days * PAH requiring pharmacologic therapy. * Significant pulmonary disease with FVC ≤ 50% of predicted, or DLCO (uncorrected for hemoglobin ) ≤ 40% of predicted 6. Laboratory examinations \- Participants with hemoglobin \< 9.0 g/dL, white blood cell (WBC) count \< 3000/mm3 (\< 3 × 109/L), platelet count \< 100,000/mm3 (\< 3 × 109/L) at the screening visit 7. Prior and concomitant therapy * Concomitant use of nitrates or NO donors (such as amyl nitrate) in any form, including topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as sildenafil, tadalafil, vardenafil); and nonspecific PDE5 inhibitors (theophylline,dipyridamole). If the patient is on PDE5 inhibitors, a wash out of 3 days is required for sildenafil and 7 days for tadalafil or vardenafil prior to the baseline visit * Concomitant Endothelin receptor antagonist * Patients who are actively smoking at time of consent. (Quit date of two weeks prior to screening acceptable) 8. Pregnant or breastfeeding women 9. Other * Any other condition or therapy that would make the participant unsuitable for this study and will not allow participation for the full planned study period * Participation in another clinical study with an investigational drug or medical device within 30 days prior to randomization (phase I-III clinical studies)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Double-blind Treatment (Week 16) in Digital Ulcer Net Burden | Baseline to Week 16 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Healing of All DUs at Baseline by Week 16 | Week 16 | 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. |
| Proportion of Participants With no DUs at Week 16 | Week 16 | 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. |
| Proportion of Participants With New Active and Indeterminate DU(s) Over the Course of the Double-blind Period | Baseline to Week 16 | 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. |
| Proportion of Participants Who Develop Pressure Ulcers at Distal Interphalangeal (DIP) Location Over the Course of the Double-blind Period. | Baseline to Week 16 | 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. |
| Proportion of Participants Who Develop Pressure Ulcers at Proximal Interphalangeal (PIP) Location Over the Course of the Double-blind Period. | Baseline to Week 16 | 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. |
| Proportion of Participants Who Develop Pressure Ulcers at Metacarpophalangeal (MCPs) Location Over the Course of the Double-blind Period. | Baseline to Week 16 | 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. |
| Proportion of Participants Who Develop Pressure Ulcers at the Elbows Over the Course of the Double-blind Period. | Baseline to Week 16 | 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. |
| Proportion of Participants With Healing of All Pressure Ulcers at the Distal Interphalangeal (DIP) Over the Course of the Double-blind Period. | Baseline to Week 16 | 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. |
| Proportion of Participants With Healing of All Pressure Ulcers at the Proximal Interphalangeal (PIP) Over the Course of the Double-blind Period. | Baseline to Week 16 | 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. |
| Proportion of Participants With Healing of All Pressure Ulcers at the Metacarpophalangeal (MCPs) Over the Course of the Double-blind Period. | Baseline to Week 16 | 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. |
| Proportion of Participants With Healing of All Pressure Ulcers at the Elbows Over the Course of the Double-blind Period. | Baseline to Week 16 | 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. |
| Time to Healing of Cardinal DU | Baseline to Week 16 | 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. |
| Time to Healing of All Baseline DU | Baseline to Week 16 | 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. |
| Time to Development of New ('Active' or 'Indeterminate') DU | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Raynaud's Condition Score | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Number of Raynaud's Attacks/Day | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Duration of Raynaud's Attacks | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Patient's Assessment of Pain During a Raynaud's Attack | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Patient's Assessment of Numbness During a Raynaud's Attack | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Patient's Assessment of Tingling During a Raynaud's Attack | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Patient's Assessment of Severity of Digital Ulcers | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Physician's Assessment of Severity of Raynaud's Disease | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Physician's Assessment of Severity of Digital Ulcers | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Patient's Assessment of Severity of Raynaud's Disease | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Patient's Global Assessment for Overall Disease. | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Physician's Global Assessment for Overall Disease. | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in PROMIS-29 Physical Function | Baseline/Week 16 | 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). |
| Change From Baseline to Week 16 in PROMIS-29 Anxiety | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in PROMIS-29 Depression | Baseline to Week 16 | 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). |
| Change From Baseline to Week 16 in PROMIS-29 Fatigue | Baseline to Week 16 | 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). |
| Change From Baseline to Week 16 in PROMIS-29 Sleep Disturbance | Baseline/Week 16 | 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). |
| Change From Baseline to Week 16 in PROMIS-29 Pain Interference | Baseline to Week 16 | 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). |
| Change From Baseline to Week 16 in PROMIS-29 Ability to Participate in Social Roles and Activities | Baseline to Week 16 | 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). |
| Change From Baseline to Week 16 in PROMIS-29 Pain Intensity | Baseline to Week 16 | 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). |
| Change From Baseline to Week 16 in Overall HAQ-DI Score | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Dressing and Grooming | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Hygiene | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Arising | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Reach | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Eating | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Grip | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Walking | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Common Daily Activities (IADL). | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in HAQ-DI Composite Score for Hand Function | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Total Hand Disability in Systemic Sclerosis-DU (HDISS-DU) Score | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Burden of Digital Ulcers | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Raynaud's Disease | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Gastrointestinal Involvement | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Breathing | Baseline to Week 16 | 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. |
| Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Overall Disease, | Baseline to Week 16 | 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. |
| Proportion of Participants Who Experience Digital Ischemia Requiring Intravenous Prostacyclin or Digital Gangrene or Amputation During the Trial. | Baseline to Week 16 | 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 |
| Proportion of Participants With Healing of Their Cardinal DU by Week 16 | Week 16 | 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. |
| Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma | Baseline and Week 16 | — |
| Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma | Baseline and Week 16 | — |
| Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma | Baseline and Week 16 | — |
| Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma | Baseline and Week 16 | — |
| Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma | Baseline and Week 16 | — |
| Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma | Baseline and Week 16 | — |
| Proportion of Participants Who Develop Osteomyelitis During The Trial | Baseline to Week 16 | The proportion of participants who developed osteomyelitis during the double-blind period of the trial. Osteomyelitis is collected as an Adverse Event. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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) | 9 |
| 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; | 8 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Riociguat | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 14 | 61 years STANDARD_DEVIATION 17 | 51 years STANDARD_DEVIATION 18 |
| Age, Customized Age Categories 18 to 35 years | 4 Participants | 1 Participants | 5 Participants |
| Age, Customized Age Categories >35 to 55 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Customized Age Categories >55 to 75 years | 2 Participants | 5 Participants | 7 Participants |
| Age, Customized Age Categories >75 years | 0 Participants | 1 Participants | 1 Participants |
| Baseline use of vasodilators | 1 Participants | 1 Participants | 2 Participants |
| Duration of Raynaud's attacks | 101.4 minutes STANDARD_DEVIATION 117.3 | 47.9 minutes STANDARD_DEVIATION 51.6 | 76.4 minutes STANDARD_DEVIATION 93.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 8 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of digital ulcers at screening | 2.67 number of digital ulcers STANDARD_DEVIATION 1.803 | 2.50 number of digital ulcers STANDARD_DEVIATION 1.69 | 2.59 number of digital ulcers STANDARD_DEVIATION 1.698 |
| Number of Raynaud's attacks per day | 4.3 attacks per day STANDARD_DEVIATION 1.7 | 2.2 attacks per day STANDARD_DEVIATION 1.7 | 3.3 attacks per day STANDARD_DEVIATION 2 |
| Numbness during a Raynaud's attack | 40.5 units on a scale STANDARD_DEVIATION 15.9 | 32.0 units on a scale STANDARD_DEVIATION 30.2 | 36.5 units on a scale STANDARD_DEVIATION 23.2 |
| Pain during a Raynaud's attack | 54.9 units on a scale STANDARD_DEVIATION 13.1 | 37.2 units on a scale STANDARD_DEVIATION 24.6 | 46.6 units on a scale STANDARD_DEVIATION 20.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 7 Participants | 13 Participants |
| Raynaud's condition score | 3.4 units on a scale STANDARD_DEVIATION 2.2 | 5.4 units on a scale STANDARD_DEVIATION 1.6 | 4.5 units on a scale STANDARD_DEVIATION 2.1 |
| Severity of patient assessment of digital ulcers | 8.0 units on a scale STANDARD_DEVIATION 1.5 | 6.7 units on a scale STANDARD_DEVIATION 1.9 | 7.4 units on a scale STANDARD_DEVIATION 1.8 |
| Severity of patient assessment of Raynaud's phenomenon | 7.1 units on a scale STANDARD_DEVIATION 1.4 | 4.2 units on a scale STANDARD_DEVIATION 2.7 | 5.8 units on a scale STANDARD_DEVIATION 2.5 |
| Severity of physician assessment of digital ulcers | 6.4 units on a scale STANDARD_DEVIATION 1.9 | 6.3 units on a scale STANDARD_DEVIATION 2.6 | 6.4 units on a scale STANDARD_DEVIATION 2.1 |
| Severity of physician assessment of Raynaud's phenomenon | 6.1 units on a scale STANDARD_DEVIATION 1 | 5.4 units on a scale STANDARD_DEVIATION 3 | 5.8 units on a scale STANDARD_DEVIATION 2.1 |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
| SHAQ: Finger ulcers interfere with daily activities in past week | 116 units on a scale | 55 units on a scale | 98 units on a scale |
| Systemic scleroderma-related antibodies Anti-centromere B | 3 Participants | 3 Participants | 6 Participants |
| Systemic scleroderma-related antibodies Anti-RNA polymerase III | 1 Participants | 0 Participants | 1 Participants |
| Systemic scleroderma-related antibodies Anti-topoisomerase I | 2 Participants | 3 Participants | 5 Participants |
| Systemic scleroderma-related antibodies Not done | 3 Participants | 2 Participants | 5 Participants |
| Time since first Digital Ulcer | 5.41 years STANDARD_DEVIATION 4.563 | 8.07 years STANDARD_DEVIATION 6.842 | 6.66 years STANDARD_DEVIATION 5.725 |
| Time since first non-Raynaud's Symptom | 7.09 years STANDARD_DEVIATION 5.933 | 17.49 years STANDARD_DEVIATION 11.09 | 11.98 years STANDARD_DEVIATION 10.06 |
| Time since first Raynaud's Phenomenon symptom | 7.49 years STANDARD_DEVIATION 6.649 | 14.5 years STANDARD_DEVIATION 7.872 | 11.01 years STANDARD_DEVIATION 7.92 |
| Time since Scleroderma Diagnosis | 6.23 years STANDARD_DEVIATION 5.765 | 15.0 years STANDARD_DEVIATION 8.05 | 10.37 years STANDARD_DEVIATION 8.156 |
| Tingling during a Raynaud's attack | 34.8 units on a scale STANDARD_DEVIATION 16.6 | 26.9 units on a scale STANDARD_DEVIATION 16.1 | 31.1 units on a scale STANDARD_DEVIATION 16.3 |
| Type of scleroderma at screening diffuse cutaneous | 4 Participants | 4 Participants | 8 Participants |
| Type of scleroderma at screening limited cutaneous | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 8 |
| other Total, other adverse events | 9 / 9 | 8 / 8 |
| serious Total, serious adverse events | 3 / 9 | 1 / 8 |
Outcome results
Primary
Change From Baseline to End of Double-blind Treatment (Week 16) in Digital Ulcer Net Burden
Digital ulcer net burden is defined as the total number of active and indeterminate digital ulcers at an assessment. 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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to End of Double-blind Treatment (Week 16) in Digital Ulcer Net Burden | -1.22 ulcers | Standard Error 0.458 |
| Placebo | Change From Baseline to End of Double-blind Treatment (Week 16) in Digital Ulcer Net Burden | -0.98 ulcers | Standard Error 0.425 |
p-value: 0.7ANCOVA
Secondary
Change From Baseline to Week 16 in Duration of Raynaud's Attacks
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Duration of Raynaud's Attacks | -44.81 minutes | Standard Error 15.846 |
| Placebo | Change From Baseline to Week 16 in Duration of Raynaud's Attacks | 150.3 minutes | Standard Error 15.846 |
p-value: 0.4ANCOVA
Secondary
Change From Baseline to Week 16 in HAQ-DI Arising
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Arising | 0.36 score on a scale | Standard Error 0.235 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Arising | 0.02 score on a scale | Standard Error 0.251 |
p-value: 0.34ANCOVA
Secondary
Change From Baseline to Week 16 in HAQ-DI Common Daily Activities (IADL).
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Common Daily Activities (IADL). | -0.29 score on a scale | Standard Error 0.26 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Common Daily Activities (IADL). | 0.04 score on a scale | Standard Error 0.278 |
p-value: 0.41ANCOVA
Secondary
Change From Baseline to Week 16 in HAQ-DI Composite Score for Hand Function
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Composite Score for Hand Function | -0.47 score on a scale | Standard Error 0.492 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Composite Score for Hand Function | -0.32 score on a scale | Standard Error 0.527 |
p-value: 0.85ANCOVA
Secondary
Change From Baseline to Week 16 in HAQ-DI Dressing and Grooming
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Dressing and Grooming | -0.16 score on a scale | Standard Error 0.18 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Dressing and Grooming | 0.05 score on a scale | Standard Error 0.236 |
p-value: 0.55ANCOVA
Secondary
Change From Baseline to Week 16 in HAQ-DI Eating
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Eating | -0.53 score on a scale | Standard Error 0.154 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Eating | 0.03 score on a scale | Standard Error 0.166 |
p-value: 0.04ANCOVA
Secondary
Change From Baseline to Week 16 in HAQ-DI Grip
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Grip | 0.16 score on a scale | Standard Error 0.215 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Grip | -0.18 score on a scale | Standard Error 0.23 |
p-value: 0.32ANCOVA
Secondary
Change From Baseline to Week 16 in HAQ-DI Hygiene
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Hygiene | -0.39 score on a scale | Standard Error 0.279 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Hygiene | -0.27 score on a scale | Standard Error 0.298 |
Secondary
Change From Baseline to Week 16 in HAQ-DI Reach
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Reach | 0.37 score on a scale | Standard Error 0.253 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Reach | 0.01 score on a scale | Standard Error 0.271 |
p-value: 0.36ANCOVA
Secondary
Change From Baseline to Week 16 in HAQ-DI Walking
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in HAQ-DI Walking | 0.35 score on a scale | Standard Error 0.199 |
| Placebo | Change From Baseline to Week 16 in HAQ-DI Walking | -0.12 score on a scale | Standard Error 0.214 |
p-value: 0.14ANCOVA
Secondary
Change From Baseline to Week 16 in Number of Raynaud's Attacks/Day
The mean number of Raynaud's attacks each day will be calculated across the 7-day screening and week 16 periods for each participant. For the days when a participant does not have an attack, a score of 0 will be used.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Number of Raynaud's Attacks/Day | -1.24 attacks per day | Standard Error 0.323 |
| Placebo | Change From Baseline to Week 16 in Number of Raynaud's Attacks/Day | -0.96 attacks per day | Standard Error 0.323 |
p-value: 0.57ANCOVA
Secondary
Change From Baseline to Week 16 in Overall HAQ-DI Score
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Overall HAQ-DI Score | -0.01 score on a scale | Standard Error 0.149 |
| Placebo | Change From Baseline to Week 16 in Overall HAQ-DI Score | -0.06 score on a scale | Standard Error 0.16 |
p-value: 0.84ANCOVA
Secondary
Change From Baseline to Week 16 in Patient's Assessment of Numbness During a Raynaud's Attack
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Patient's Assessment of Numbness During a Raynaud's Attack | -15.44 units on a scale | Standard Error 8.899 |
p-value: 0.75ANCOVA
Secondary
Change From Baseline to Week 16 in Patient's Assessment of Pain During a Raynaud's Attack
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 6.6 |
| Placebo | Change From Baseline to Week 16 in Patient's Assessment of Pain During a Raynaud's Attack | -7.01 units on a scale | Standard Error 6.6 |
p-value: 0.49ANCOVA
Secondary
Change From Baseline to Week 16 in Patient's Assessment of Severity of Digital Ulcers
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.
Time frame: Baseline to Week 16
Population: Severity of digital ulcer(s) is calculated as the mean response on a 0-10 Likert scale.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Patient's Assessment of Severity of Digital Ulcers | -4.00 units on a scale | Standard Error 0.935 |
p-value: 0.66ANCOVA
Secondary
Change From Baseline to Week 16 in Patient's Assessment of Severity of Raynaud's Disease
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.
Time frame: Baseline to Week 16
Population: Severity of Raynaud's disease is calculated as the mean response on a 0-10 Likert scale.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Patient's Assessment of Severity of Raynaud's Disease | -1.41 units on a scale | Standard Error 0.764 |
p-value: 0.11ANCOVA
Secondary
Change From Baseline to Week 16 in Patient's Assessment of Tingling During a Raynaud's Attack
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Patient's Assessment of Tingling During a Raynaud's Attack | -7.49 units on a scale | Standard Error 7.118 |
p-value: 0.41ANCOVA
Secondary
Change From Baseline to Week 16 in Patient's Global Assessment for Overall Disease.
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Patient's Global Assessment for Overall Disease. | 0.31 units on a scale | Standard Error 0.915 |
| Placebo | Change From Baseline to Week 16 in Patient's Global Assessment for Overall Disease. | -1.19 units on a scale | Standard Error 0.915 |
p-value: 0.27ANCOVA
Secondary
Change From Baseline to Week 16 in Physician's Assessment of Severity of Digital Ulcers
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Physician's Assessment of Severity of Digital Ulcers | -3.81 units on a scale | Standard Error 0.948 |
p-value: 0.84ANCOVA
Secondary
Change From Baseline to Week 16 in Physician's Assessment of Severity of Raynaud's Disease
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Physician's Assessment of Severity of Raynaud's Disease | -1.86 units on a scale | Standard Error 0.788 |
p-value: 0.31ANCOVA
Secondary
Change From Baseline to Week 16 in Physician's Global Assessment for Overall Disease.
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Physician's Global Assessment for Overall Disease. | -1.17 units on a scale | Standard Error 0.548 |
| Placebo | Change From Baseline to Week 16 in Physician's Global Assessment for Overall Disease. | -0.66 units on a scale | Standard Error 0.586 |
p-value: 0.54ANCOVA
Secondary
Change From Baseline to Week 16 in PROMIS-29 Ability to Participate in Social Roles and Activities
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).
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in PROMIS-29 Ability to Participate in Social Roles and Activities | -0.46 t-score | Standard Error 1.104 |
p-value: 0.47ANCOVA
Secondary
Change From Baseline to Week 16 in PROMIS-29 Anxiety
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in PROMIS-29 Anxiety | -3.11 t-score | Standard Error 2.578 |
| Placebo | Change From Baseline to Week 16 in PROMIS-29 Anxiety | -1.50 t-score | Standard Error 2.578 |
p-value: 0.68ANCOVA
Secondary
Change From Baseline to Week 16 in PROMIS-29 Depression
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).
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in PROMIS-29 Depression | -3.35 t-score | Standard Error 1.731 |
| Placebo | Change From Baseline to Week 16 in PROMIS-29 Depression | -0.25 t-score | Standard Error 1.731 |
p-value: 0.25ANCOVA
Secondary
Change From Baseline to Week 16 in PROMIS-29 Fatigue
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).
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in PROMIS-29 Fatigue | 0.64 t-score | Standard Error 1.903 |
| Placebo | Change From Baseline to Week 16 in PROMIS-29 Fatigue | 0.46 t-score | Standard Error 1.903 |
p-value: 0.95ANCOVA
Secondary
Change From Baseline to Week 16 in PROMIS-29 Pain Intensity
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).
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in PROMIS-29 Pain Intensity | -2.74 t-score | Standard Error 0.702 |
| Placebo | Change From Baseline to Week 16 in PROMIS-29 Pain Intensity | -1.63 t-score | Standard Error 0.702 |
p-value: 0.35ANCOVA
Secondary
Change From Baseline to Week 16 in PROMIS-29 Pain Interference
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).
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in PROMIS-29 Pain Interference | -3.69 t-score | Standard Error 1.798 |
| Placebo | Change From Baseline to Week 16 in PROMIS-29 Pain Interference | -3.06 t-score | Standard Error 1.798 |
p-value: 0.82ANCOVA
Secondary
Change From Baseline to Week 16 in PROMIS-29 Physical Function
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).
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in PROMIS-29 Physical Function | -2.46 t-score | Standard Error 1.27 |
| Placebo | Change From Baseline to Week 16 in PROMIS-29 Physical Function | -2.24 t-score | Standard Error 1.227 |
p-value: 0.9ANCOVA
Secondary
Change From Baseline to Week 16 in PROMIS-29 Sleep Disturbance
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).
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in PROMIS-29 Sleep Disturbance | -0.47 t-score | Standard Error 1.091 |
| Placebo | Change From Baseline to Week 16 in PROMIS-29 Sleep Disturbance | 0.94 t-score | Standard Error 1.091 |
p-value: 0.38ANCOVA
Secondary
Change From Baseline to Week 16 in Raynaud's Condition Score
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Raynaud's Condition Score | -1.15 units on a scale | Standard Error 0.691 |
| Placebo | Change From Baseline to Week 16 in Raynaud's Condition Score | -0.82 units on a scale | Standard Error 0.691 |
p-value: 0.76ANCOVA
Secondary
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Breathing
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Breathing | 8.35 score on a scale | Standard Error 8.9 |
| Placebo | Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Breathing | -12.69 score on a scale | Standard Error 8.978 |
p-value: 0.14ANCOVA
Secondary
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Burden of Digital Ulcers
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Burden of Digital Ulcers | -53.47 score on a scale | Standard Error 20.159 |
p-value: 0.75ANCOVA
Secondary
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Gastrointestinal Involvement
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.
Time frame: 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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Gastrointestinal Involvement | -7.39 score on a scale | Standard Error 14.975 |
p-value: 0.31ANCOVA
Secondary
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Overall Disease,
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Overall Disease, | -35.74 score on a scale | Standard Error 9.751 |
p-value: 0.32ANCOVA
Secondary
Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Raynaud's Disease
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Raynaud's Disease | -25.40 score on a scale | Standard Error 16.982 |
p-value: 0.95ANCOVA
Secondary
Change From Baseline to Week 16 in Total Hand Disability in Systemic Sclerosis-DU (HDISS-DU) Score
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | 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 |
| Placebo | Change From Baseline to Week 16 in Total Hand Disability in Systemic Sclerosis-DU (HDISS-DU) Score | -0.32 score on a scale | Standard Error 0.527 |
p-value: 0.85ANCOVA
Secondary
Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma
Time frame: Baseline and Week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma | 0.20 pg/ml | Standard Error 0.28 |
| Placebo | Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma | -0.03 pg/ml | Standard Error 0.29 |
p-value: 0.58ANCOVA
Secondary
Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma | 70.5 ng/ml | Standard Error 47.3 |
| Placebo | Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma | -39. ng/ml | Standard Error 50.2 |
p-value: 0.14ANCOVA
Secondary
Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma | -4.7 ng/ml | Standard Error 1.9 |
| Placebo | Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma | -2.5 ng/ml | Standard Error 2 |
p-value: 0.45ANCOVA
Secondary
Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma | -1.2 ng/ml | Standard Error 0.5 |
| Placebo | Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma | -0.5 ng/ml | Standard Error 0.5 |
p-value: 0.32ANCOVA
Secondary
Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma | 10.3 ng/ml | Standard Error 10.4 |
| Placebo | Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma | -3.4 ng/ml | Standard Error 11 |
p-value: 0.39ANCOVA
Secondary
Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riociguat | Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma | -29.8 pg/ml | Standard Error 9.5 |
| Placebo | Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma | -34.7 pg/ml | Standard Error 10.1 |
p-value: 0.73ANCOVA
Secondary
Proportion of Participants Who Develop Osteomyelitis During The Trial
The proportion of participants who developed osteomyelitis during the double-blind period of the trial. Osteomyelitis is collected as an Adverse Event.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants Who Develop Osteomyelitis During The Trial | 0 Participants |
| Placebo | Proportion of Participants Who Develop Osteomyelitis During The Trial | 0 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants Who Develop Pressure Ulcers at Distal Interphalangeal (DIP) Location Over the Course of the Double-blind Period.
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants Who Develop Pressure Ulcers at Distal Interphalangeal (DIP) Location Over the Course of the Double-blind Period. | 0 Participants |
| Placebo | Proportion of Participants Who Develop Pressure Ulcers at Distal Interphalangeal (DIP) Location Over the Course of the Double-blind Period. | 1 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants Who Develop Pressure Ulcers at Metacarpophalangeal (MCPs) Location Over the Course of the Double-blind Period.
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants Who Develop Pressure Ulcers at Metacarpophalangeal (MCPs) Location Over the Course of the Double-blind Period. | 0 Participants |
| Placebo | Proportion of Participants Who Develop Pressure Ulcers at Metacarpophalangeal (MCPs) Location Over the Course of the Double-blind Period. | 0 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants Who Develop Pressure Ulcers at Proximal Interphalangeal (PIP) Location Over the Course of the Double-blind Period.
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants Who Develop Pressure Ulcers at Proximal Interphalangeal (PIP) Location Over the Course of the Double-blind Period. | 1 Participants |
| Placebo | Proportion of Participants Who Develop Pressure Ulcers at Proximal Interphalangeal (PIP) Location Over the Course of the Double-blind Period. | 2 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants Who Develop Pressure Ulcers at the Elbows Over the Course of the Double-blind Period.
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants Who Develop Pressure Ulcers at the Elbows Over the Course of the Double-blind Period. | 0 Participants |
| Placebo | Proportion of Participants Who Develop Pressure Ulcers at the Elbows Over the Course of the Double-blind Period. | 0 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants Who Experience Digital Ischemia Requiring Intravenous Prostacyclin or Digital Gangrene or Amputation During the Trial.
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
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants Who Experience Digital Ischemia Requiring Intravenous Prostacyclin or Digital Gangrene or Amputation During the Trial. | 0 Participants |
| Placebo | Proportion of Participants Who Experience Digital Ischemia Requiring Intravenous Prostacyclin or Digital Gangrene or Amputation During the Trial. | 1 Participants |
p-value: 0.47Fisher Exact
Secondary
Proportion of Participants With Healing of All DUs at Baseline by Week 16
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants With Healing of All DUs at Baseline by Week 16 | 3 Participants |
| Placebo | Proportion of Participants With Healing of All DUs at Baseline by Week 16 | 3 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants With Healing of All Pressure Ulcers at the Distal Interphalangeal (DIP) Over the Course of the Double-blind Period.
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants With Healing of All Pressure Ulcers at the Distal Interphalangeal (DIP) Over the Course of the Double-blind Period. | 0 Participants |
| Placebo | Proportion of Participants With Healing of All Pressure Ulcers at the Distal Interphalangeal (DIP) Over the Course of the Double-blind Period. | 0 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants With Healing of All Pressure Ulcers at the Elbows Over the Course of the Double-blind Period.
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants With Healing of All Pressure Ulcers at the Elbows Over the Course of the Double-blind Period. | 0 Participants |
| Placebo | Proportion of Participants With Healing of All Pressure Ulcers at the Elbows Over the Course of the Double-blind Period. | 0 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants With Healing of All Pressure Ulcers at the Metacarpophalangeal (MCPs) Over the Course of the Double-blind Period.
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants With Healing of All Pressure Ulcers at the Metacarpophalangeal (MCPs) Over the Course of the Double-blind Period. | 0 Participants |
| Placebo | Proportion of Participants With Healing of All Pressure Ulcers at the Metacarpophalangeal (MCPs) Over the Course of the Double-blind Period. | 0 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants With Healing of All Pressure Ulcers at the Proximal Interphalangeal (PIP) Over the Course of the Double-blind Period.
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants With Healing of All Pressure Ulcers at the Proximal Interphalangeal (PIP) Over the Course of the Double-blind Period. | 1 Participants |
| Placebo | Proportion of Participants With Healing of All Pressure Ulcers at the Proximal Interphalangeal (PIP) Over the Course of the Double-blind Period. | 0 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants With Healing of Their Cardinal DU by Week 16
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants With Healing of Their Cardinal DU by Week 16 | 4 Participants |
| Placebo | Proportion of Participants With Healing of Their Cardinal DU by Week 16 | 6 Participants |
p-value: 0.61Fisher Exact
Secondary
Proportion of Participants With New Active and Indeterminate DU(s) Over the Course of the Double-blind Period
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants With New Active and Indeterminate DU(s) Over the Course of the Double-blind Period | 3 Participants |
| Placebo | Proportion of Participants With New Active and Indeterminate DU(s) Over the Course of the Double-blind Period | 4 Participants |
p-value: 1Fisher Exact
Secondary
Proportion of Participants With no DUs at Week 16
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Proportion of Participants With no DUs at Week 16 | 2 Participants |
| Placebo | Proportion of Participants With no DUs at Week 16 | 2 Participants |
p-value: 1Fisher Exact
Secondary
Time to Development of New ('Active' or 'Indeterminate') DU
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Riociguat | Time to Development of New ('Active' or 'Indeterminate') DU | 16.00 weeks |
| Placebo | Time to Development of New ('Active' or 'Indeterminate') DU | 15.86 weeks |
Secondary
Time to Healing of All Baseline DU
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Riociguat | Time to Healing of All Baseline DU | 16.00 weeks |
| Placebo | Time to Healing of All Baseline DU | 16.00 weeks |
p-value: 0.35Log Rank
Secondary
Time to Healing of Cardinal DU
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Riociguat | Time to Healing of Cardinal DU | 16.57 weeks |
| Placebo | Time to Healing of Cardinal DU | 16.07 weeks |
p-value: 0.56Log Rank