Clinical trial NCT02915835: Riociguat in Scleroderma Associated Digital Ulcers
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Scleroderma
Digital Ulcers
Keywords: Scleroderma
Digital Ulcer
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2016-09-27
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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)

Primary outcomes:
measure: Change From Baseline to End of Double-blind Treatment (Week 16) in Digital Ulcer Net Burden
timeFrame: Baseline to Week 16
Secondary outcomes:
measure: Proportion of Participants With Healing of Their Cardinal DU by Week 16
timeFrame: Week 16
measure: Proportion of Participants With Healing of All DUs at Baseline by Week 16
timeFrame: Week 16
measure: Proportion of Participants With no DUs at Week 16
timeFrame: Week 16
measure: Proportion of Participants With New Active and Indeterminate DU(s) Over the Course of the Double-blind Period
timeFrame: Baseline to Week 16
measure: Proportion of Participants Who Develop Pressure Ulcers at Distal Interphalangeal (DIP) Location Over the Course of the Double-blind Period.
timeFrame: Baseline to Week 16
measure: Proportion of Participants Who Develop Pressure Ulcers at Proximal Interphalangeal (PIP) Location Over the Course of the Double-blind Period.
timeFrame: Baseline to Week 16
measure: Proportion of Participants Who Develop Pressure Ulcers at Metacarpophalangeal (MCPs) Location Over the Course of the Double-blind Period.
timeFrame: Baseline to Week 16
measure: Proportion of Participants Who Develop Pressure Ulcers at the Elbows Over the Course of the Double-blind Period.
timeFrame: Baseline to Week 16
measure: Proportion of Participants With Healing of All Pressure Ulcers at the Distal Interphalangeal (DIP) Over the Course of the Double-blind Period.
timeFrame: Baseline to Week 16
measure: Proportion of Participants With Healing of All Pressure Ulcers at the Proximal Interphalangeal (PIP) Over the Course of the Double-blind Period.
timeFrame: Baseline to Week 16
measure: Proportion of Participants With Healing of All Pressure Ulcers at the Metacarpophalangeal (MCPs) Over the Course of the Double-blind Period.
timeFrame: Baseline to Week 16
measure: Proportion of Participants With Healing of All Pressure Ulcers at the Elbows Over the Course of the Double-blind Period.
timeFrame: Baseline to Week 16
measure: Time to Healing of Cardinal DU
timeFrame: Baseline to Week 16
measure: Time to Healing of All Baseline DU
timeFrame: Baseline to Week 16
measure: Time to Development of New ('Active' or 'Indeterminate') DU
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Raynaud's Condition Score
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Number of Raynaud's Attacks/Day
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Duration of Raynaud's Attacks
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Patient's Assessment of Pain During a Raynaud's Attack
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Patient's Assessment of Numbness During a Raynaud's Attack
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Patient's Assessment of Tingling During a Raynaud's Attack
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Physician's Assessment of Severity of Raynaud's Disease
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Physician's Assessment of Severity of Digital Ulcers
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Patient's Assessment of Severity of Raynaud's Disease
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Patient's Assessment of Severity of Digital Ulcers
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Patient's Global Assessment for Overall Disease.
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Physician's Global Assessment for Overall Disease.
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in PROMIS-29 Physical Function
timeFrame: Baseline/Week 16
measure: Change From Baseline to Week 16 in PROMIS-29 Anxiety
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in PROMIS-29 Depression
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in PROMIS-29 Fatigue
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in PROMIS-29 Sleep Disturbance
timeFrame: Baseline/Week 16
measure: Change From Baseline to Week 16 in PROMIS-29 Pain Interference
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in PROMIS-29 Ability to Participate in Social Roles and Activities
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in PROMIS-29 Pain Intensity
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Overall HAQ-DI Score
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Dressing and Grooming
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Hygiene
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Arising
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Reach
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Eating
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Grip
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Walking
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Common Daily Activities (IADL).
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in HAQ-DI Composite Score for Hand Function
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Total Hand Disability in Systemic Sclerosis-DU (HDISS-DU) Score
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Burden of Digital Ulcers
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Raynaud's Disease
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Gastrointestinal Involvement
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Breathing
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Scleroderma-HAQ-DI Visual Analogue Scales (VAS) Assessing Overall Disease,
timeFrame: Baseline to Week 16
measure: Proportion of Participants Who Experience Digital Ischemia Requiring Intravenous Prostacyclin or Digital Gangrene or Amputation During the Trial.
timeFrame: Baseline to Week 16
measure: Proportion of Participants Who Develop Osteomyelitis During The Trial
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in Vascular Biomarker VEGF in the Plasma
timeFrame: Baseline and Week 16
measure: Change From Baseline to Week 16 in Vascular Biomarker tPA in the Plasma
timeFrame: Baseline and Week 16
measure: Change From Baseline to Week 16 in Vascular Biomarker sE-Selectin in the Plasma
timeFrame: Baseline and Week 16
measure: Change From Baseline to Week 16 in Vascular Biomarker BFGF in the Plasma
timeFrame: Baseline and Week 16
measure: Change From Baseline to Week 16 in Vascular Biomarker VCAM-1 in the Plasma
timeFrame: Baseline and Week 16
measure: Change From Baseline to Week 16 in Vascular Biomarker ICAM in the Plasma
timeFrame: Baseline and Week 16
Other outcomes:
Locations:
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Hospital of Special Surgery (HSS)
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Michigan
name: Dinesh Khanna, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.