Riociguat in Scleroderma Associated Digital Ulcers

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

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

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

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)