Intervention: Riociguat
Trial phase: Phase 2
ATC code: C02KX05
SMILES: COC(=O)N(C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 9
Group 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)

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)
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)