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Trial record 1 of 2 for:    riociguat scleroderma
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Riociguat in Scleroderma Associated Digital Ulcers (RESCUE)

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ClinicalTrials.gov Identifier: NCT02915835
Recruitment Status : Completed
First Posted : September 27, 2016
Results First Posted : September 24, 2019
Last Update Posted : September 24, 2019
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
Dinesh Khanna, MD, MS, University of Michigan

Tracking Information
First Submitted Date  ICMJE September 15, 2016
First Posted Date  ICMJE September 27, 2016
Results First Submitted Date  ICMJE July 25, 2019
Results First Posted Date  ICMJE September 24, 2019
Last Update Posted Date September 24, 2019
Study Start Date  ICMJE September 2016
Actual Primary Completion Date July 24, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 3, 2019)
Change From Baseline to End of Double-blind Treatment (Week 16) in Digital Ulcer Net Burden [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 22, 2016)
The primary efficacy outcome is the change from baseline to end of double-blind treatment in digital ulcer net burden. [ Time Frame: Baseline/Week 16 ]
Digital ulcer net burden is defined as the total number of "new" or "active" digital ulcers at an assessment, plus the number of "indeterminate" ulcers that had previously been classified as either "active" or "new" at any earlier assessment during the study
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 3, 2019)
  • Proportion of Participants With Healing of Their Cardinal DU by Week 16 [ Time Frame: 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.
  • Proportion of Participants With Healing of All DUs at Baseline by Week 16 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 Physician's Assessment of Severity of Raynaud's Disease [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 Assessment of Severity of Digital Ulcers [ Time Frame: 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 Patient's Global Assessment for Overall Disease. [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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). [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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, [ Time Frame: 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. [ Time Frame: 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 Who Develop Osteomyelitis During The Trial [ Time Frame: 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.
  • Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma [ Time Frame: Baseline and Week 16 ]
  • Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma [ Time Frame: Baseline and Week 16 ]
  • Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma [ Time Frame: Baseline and Week 16 ]
  • Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma [ Time Frame: Baseline and Week 16 ]
  • Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma [ Time Frame: Baseline and Week 16 ]
  • Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma [ Time Frame: Baseline and Week 16 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2016)
  • Healing of cardinal DU [ Time Frame: Baseline/Week 16 ]
    For each participant, one digital ulcer must be identified and designated by the investigator as the cardinal ulcer at Baseline. The cardinal ulcer must have met the qualifications for designation as an active ulcer. If only one ulcer was determined at entry to be active, it will be designated as the cardinal ulcer. If several digital ulcers qualified, the cardinal ulcer could be either the largest or the most painful ulcer, or the ulcer that disturbed the patient the most. The cardinal ulcer will be selected by the investigator based on the clinical judgment that it was amenable to and evaluable for healing.
  • Development of DU [ Time Frame: Baseline/Week 16 ]
  • Development and healing of pressure ulcers over the Distal Interphalangeal (DIP), Proximal Interphalangeal (PIP), Metacarpophalangeal (MCPs) and elbows [ Time Frame: Baseline/Week 16 ]
  • Time to healing of cardinal DU [ Time Frame: Baseline/Week 16 ]
  • Time to healing of all DU [ Time Frame: Baseline/Week 16 ]
  • Improvement of Raynaud's phenomenon (RP) [ Time Frame: Baseline/Week 16 ]
    Improvement in Raynaud's phenomenon will use the composite of the following 6 individual measures: Raynaud's condition score, patient assessment severity of Raynaud's phenomenon, physician assessment severity of Raynaud's phenomenon, severity of attack symptoms from patient diary, duration of attacks from patient diary, and number of attacks per day from patient diary.
  • Patient's and physician's global assessment on a Likert scale [ Time Frame: Baseline/Week 16 ]
  • Health-related quality of life (HRQOL) using PROMIS-29 [ Time Frame: Baseline/Week 16 ]
  • Physical function as assessed by HAQ-DI [ Time Frame: Baseline/Week 16 ]
  • Visual analog scales from scleroderma-health assessment questionnaire (SHAQ) [ Time Frame: Baseline/Week 16 ]
    This Patient Reported Outcome (PRO) will assess the burden of digital ulcers, Raynaud's disease, gastrointestinal involvement, breathing, and overall disease
  • Digital ischemia requiring intravenous prostacyclin or digital gangrene or amputation [ Time Frame: Baseline/Week 16 ]
    These will be collected within Adverse Events
  • Vascular biomarkers in the plasma [ Time Frame: Baseline/Week 16 ]
    Biomarkers: VEGF, tPA, sE-Selectin, BFGF, VCAM-1, ICAM
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Riociguat in Scleroderma Associated Digital Ulcers
Official Title  ICMJE A Multi-center Randomized, Double Blind, Placebo-controlled, Pilot Study to Assess the Efficacy and Safety of Riociguat in Scleroderma - Associated Digital Ulcers
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Scleroderma
  • Digital Ulcers
Intervention  ICMJE
  • Drug: 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)
    Other Name: Adempas
  • Drug: Placebo
    Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Study Arms  ICMJE
  • Active Comparator: 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)
    Intervention: Drug: Riociguat
  • Placebo Comparator: 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.
    Intervention: Drug: Placebo
Publications * Nagaraja V, Spino C, Bush E, Tsou PS, Domsic RT, Lafyatis R, Frech T, Gordon JK, Steen VD, Khanna D. A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers. Arthritis Res Ther. 2019 Sep 3;21(1):202. doi: 10.1186/s13075-019-1979-7.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 26, 2018)
17
Original Estimated Enrollment  ICMJE
 (submitted: September 22, 2016)
20
Actual Study Completion Date  ICMJE July 24, 2018
Actual Primary Completion Date July 24, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02915835
Other Study ID Numbers  ICMJE BAY63-2521
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Dinesh Khanna, MD, MS, University of Michigan
Study Sponsor  ICMJE Dinesh Khanna, MD, MS
Collaborators  ICMJE Bayer
Investigators  ICMJE
Principal Investigator: Dinesh Khanna, MD University of Michigan
PRS Account University of Michigan
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP