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Riociguat in Scleroderma Associated Digital Ulcers (RESCUE)

Primary Purpose

Scleroderma, Digital Ulcers

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Riociguat

Placebo

About this trial

This is an interventional treatment trial for Scleroderma focused on measuring Scleroderma, Digital Ulcer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Signed written informed consent
Men or women aged 18 years and older
Diagnosis of Systemic sclerosis, as defined by 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc
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
Females of reproductive potential (FRP) must have a negative, pre-treatment urine pregnancy test.
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.
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.)
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
Ability to comply with the clinical visits schedule and the study-related procedures.

Exclusion Criteria:

Active DU related to calcinosis (as assessed by clinical examination or radiographic evaluation at screening)
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
Hepatic-related criteria
- Hepatic insufficiency classified as Child-Pugh C at screening (see Appendix 11.1 for classification table) at screening visit
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
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
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
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)
Pregnant or breastfeeding women
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)

Sites / Locations

Georgetown University
University of Michigan
Hospital of Special Surgery (HSS)
University of Pittsburgh
University of Utah

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

riociguat

Placebo

Arm Description

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)

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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 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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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).

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).

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).

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).

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).

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).

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.

Change From Baseline to Week 16 in HAQ-DI Dressing and Grooming

Change From Baseline to Week 16 in HAQ-DI Hygiene

Change From Baseline to Week 16 in HAQ-DI Arising

Change From Baseline to Week 16 in HAQ-DI Reach

Change From Baseline to Week 16 in HAQ-DI Eating

Change From Baseline to Week 16 in HAQ-DI Grip

Change From Baseline to Week 16 in HAQ-DI Walking

Change From Baseline to Week 16 in HAQ-DI Common Daily Activities (IADL).

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.

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.

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.

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.

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.

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.

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.

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

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.

Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma

Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma

Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma

Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma

Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma

Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma

Full Information

NCT ID

NCT02915835

First Posted

September 15, 2016

Last Updated

September 3, 2019

Sponsor

Dinesh Khanna, MD, MS

Collaborators

Bayer

1. Study Identification

Unique Protocol Identification Number

NCT02915835

Brief Title

Riociguat in Scleroderma Associated Digital Ulcers

Acronym

RESCUE

Official Title

A Multi-center Randomized, Double Blind, Placebo-controlled, Pilot Study to Assess the Efficacy and Safety of Riociguat in Scleroderma - Associated Digital Ulcers

Study Type

Interventional

2. Study Status

Record Verification Date

September 2019

Overall Recruitment Status

Completed

Study Start Date

September 2016 (undefined)

Primary Completion Date

July 24, 2018 (Actual)

Study Completion Date

July 24, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Dinesh Khanna, MD, MS

Collaborators

Bayer

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Scleroderma, Digital Ulcers

Keywords

Scleroderma, Digital Ulcer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

17 (Actual)

8. Arms, Groups, and Interventions

Arm Title

riociguat

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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 Type

Drug

Intervention Name(s)

Riociguat

Other Intervention Name(s)

Adempas

Intervention Description

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 Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;

Primary Outcome Measure Information:

Title

Change From Baseline to End of Double-blind Treatment (Week 16) in Digital Ulcer Net Burden

Description

Time Frame

Baseline to Week 16

Secondary Outcome Measure Information:

Title

Proportion of Participants With Healing of Their Cardinal DU by Week 16

Description

Time Frame

Week 16

Title

Proportion of Participants With Healing of All DUs at Baseline by Week 16

Description

Time Frame

Week 16

Title

Proportion of Participants With no DUs at Week 16

Description

Time Frame

Week 16

Title

Proportion of Participants With New Active and Indeterminate DU(s) Over the Course of the Double-blind Period

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants Who Develop Pressure Ulcers at Distal Interphalangeal (DIP) Location Over the Course of the Double-blind Period.

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants Who Develop Pressure Ulcers at Proximal Interphalangeal (PIP) Location Over the Course of the Double-blind Period.

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants Who Develop Pressure Ulcers at Metacarpophalangeal (MCPs) Location Over the Course of the Double-blind Period.

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants Who Develop Pressure Ulcers at the Elbows Over the Course of the Double-blind Period.

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants With Healing of All Pressure Ulcers at the Distal Interphalangeal (DIP) Over the Course of the Double-blind Period.

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants With Healing of All Pressure Ulcers at the Proximal Interphalangeal (PIP) Over the Course of the Double-blind Period.

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants With Healing of All Pressure Ulcers at the Metacarpophalangeal (MCPs) Over the Course of the Double-blind Period.

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants With Healing of All Pressure Ulcers at the Elbows Over the Course of the Double-blind Period.

Description

Time Frame

Baseline to Week 16

Title

Time to Healing of Cardinal DU

Description

Time Frame

Baseline to Week 16

Title

Time to Healing of All Baseline DU

Description

Time Frame

Baseline to Week 16

Title

Time to Development of New ('Active' or 'Indeterminate') DU

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Raynaud's Condition Score

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Number of Raynaud's Attacks/Day

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Duration of Raynaud's Attacks

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Patient's Assessment of Pain During a Raynaud's Attack

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Patient's Assessment of Numbness During a Raynaud's Attack

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Patient's Assessment of Tingling During a Raynaud's Attack

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Physician's Assessment of Severity of Raynaud's Disease

Description

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

Title

Change From Baseline to Week 16 in Physician's Assessment of Severity of Digital Ulcers

Description

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

Title

Change From Baseline to Week 16 in Patient's Assessment of Severity of Raynaud's Disease

Description

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

Title

Change From Baseline to Week 16 in Patient's Assessment of Severity of Digital Ulcers

Description

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

Title

Change From Baseline to Week 16 in Patient's Global Assessment for Overall Disease.

Description

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

Title

Change From Baseline to Week 16 in Physician's Global Assessment for Overall Disease.

Description

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

Title

Change From Baseline to Week 16 in PROMIS-29 Physical Function

Description

Time Frame

Baseline/Week 16

Title

Change From Baseline to Week 16 in PROMIS-29 Anxiety

Description

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

Title

Change From Baseline to Week 16 in PROMIS-29 Depression

Description

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

Title

Change From Baseline to Week 16 in PROMIS-29 Fatigue

Description

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

Title

Change From Baseline to Week 16 in PROMIS-29 Sleep Disturbance

Description

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

Title

Change From Baseline to Week 16 in PROMIS-29 Pain Interference

Description

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

Title

Change From Baseline to Week 16 in PROMIS-29 Ability to Participate in Social Roles and Activities

Description

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

Title

Change From Baseline to Week 16 in PROMIS-29 Pain Intensity

Description

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

Title

Change From Baseline to Week 16 in Overall HAQ-DI Score

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Dressing and Grooming

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Hygiene

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Arising

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Reach

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Eating

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Grip

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Walking

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Common Daily Activities (IADL).

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in HAQ-DI Composite Score for Hand Function

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Total Hand Disability in Systemic Sclerosis-DU (HDISS-DU) Score

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Burden of Digital Ulcers

Description

Time Frame

Baseline to Week 16

Title

Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Raynaud's Disease

Description

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

Title

Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Gastrointestinal Involvement

Description

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

Title

Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Breathing

Description

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

Title

Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Overall Disease,

Description

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

Title

Proportion of Participants Who Experience Digital Ischemia Requiring Intravenous Prostacyclin or Digital Gangrene or Amputation During the Trial.

Description

Time Frame

Baseline to Week 16

Title

Proportion of Participants Who Develop Osteomyelitis During The Trial

Description

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

Title

Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma

Time Frame

Baseline and Week 16

Title

Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma

Time Frame

Baseline and Week 16

Title

Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma

Time Frame

Baseline and Week 16

Title

Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma

Time Frame

Baseline and Week 16

Title

Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma

Time Frame

Baseline and Week 16

Title

Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma

Time Frame

Baseline and Week 16

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Signed written informed consent Men or women aged 18 years and older Diagnosis of Systemic sclerosis, as defined by 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc 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 Females of reproductive potential (FRP) must have a negative, pre-treatment urine pregnancy test. 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. 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.) 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 Ability to comply with the clinical visits schedule and the study-related procedures. Exclusion Criteria: Active DU related to calcinosis (as assessed by clinical examination or radiographic evaluation at screening) 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 Hepatic-related criteria - Hepatic insufficiency classified as Child-Pugh C at screening (see Appendix 11.1 for classification table) at screening visit 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 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 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 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) Pregnant or breastfeeding women 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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dinesh Khanna, MD

Organizational Affiliation

University of Michigan

Official's Role

Principal Investigator

Facility Information:

Facility Name

Georgetown University

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20007

Country

United States

Facility Name

University of Michigan

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109

Country

United States

Facility Name

Hospital of Special Surgery (HSS)

City

New York

State/Province

New York

ZIP/Postal Code

10035

Country

United States

Facility Name

University of Pittsburgh

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15261

Country

United States

Facility Name

University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84132

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

31481106

Citation

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.

Results Reference

derived

Learn more about this trial

Riociguat in Scleroderma Associated Digital Ulcers

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