Riociguat in Scleroderma Associated Digital Ulcers
Condition: Scleroderma; Digital Ulcers
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized; Skin Ulcer; Ulcer
Intervention: Riociguat; Placebo
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); Placebo 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID;
Intervention MeSH terms: Riociguat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Scleroderma; Digital Ulcer

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
    

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)