A Study in People With Systemic Sclerosis to Test Whether Avenciguat (BI 685509) Has an Effect on Lung Function and Other Systemic Sclerosis Symptoms

A Phase II, Randomised, Placebo-controlled, Double-blind, Parallel Group, Efficacy and Safety Study of at Least 48 Weeks of Oral BI 685509 Treatment in Adults With Progressive Systemic Sclerosis

This study is open to adults aged 18 and older or above legal age who have systemic sclerosis. People can participate if they have a specific subtype called diffuse cutaneous systemic sclerosis. People with another subtype called limited cutaneous systemic sclerosis can also participate if they are anti Scl-70 antibody positive. Systemic sclerosis is also called scleroderma.

The purpose of this study is to find out whether a medicine called Avenciguat (BI 685509) helps people with scleroderma who have symptoms due to lung fibrosis or vascular problems.

Participants are put into 2 groups by chance. One group takes Avenciguat (BI 685509) tablets 3 times a day and the other group takes placebo tablets 3 times a day. Placebo tablets look like BI 685509 tablets but do not contain any medicine. Participants take the tablets for at least 11 months. Afterwards, participants can continue to take the tablets until the last participant has completed the 11-months treatment period. This means that the time in the study and duration of treatment is different for each participant, depending on when they start the study. At the beginning of the study, participants visit the study site every 2 weeks. The time between the visits to the study site gets longer over the course of the study. After the 11-months treatment period, participants visit the study site every 3 months.

During the study, participants regularly do lung function tests. The results are compared between the 2 groups to see whether the treatment works. The participants also regularly fill in questionnaires about their scleroderma symptoms. The doctors regularly check participants' skin condition and general health and take note of any unwanted effects.

Inclusion Criteria:

1. Signed and dated written informed consent in accordance with International Council on Harmonisation (ICH) - Good Clinical Practice (GCP) and local legislation prior to admission to the trial.

2. Male or female patients aged ≥18 years at time of consent (or above legal age, e.g. United Kingdom (UK) ≥16 years).

3. Patients must fulfill the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for Systemic sclerosis (SSc).

4. Patients must be diagnosed with limited or with diffuse cutaneous SSc as defined by LeRoy et al. (R17 0149). Patients diagnosed with limited cutaneous SSc may be included if they are anti Scl-70 antibody positive.

5. Diffuse cutaneous SSc disease onset (defined by first non-RP symptom) in patients with diffuse cutaneous SSc must be within 7 years of Visit 1. Limited cutaneous SSc onset must be within 2 years of Visit 1.

6. Evidence of active disease, defined as having at least one of the following:

   • New onset of SSc within the last 2 years of Visit 1 OR
   • New skin involvement or worsening of two new body areas within 6 months of Visit 1 (out of the possible 17 body areas defined by Modified Rodnan Skin Score (mRSS) assessment, documented in clinical files) OR
   • New involvement or worsening of one new body area if either chest or abdomen within 6 months of Visit 1 OR
   • Worsening of skin thickening (e.g. ≥2 mRSS points) within 6 months of Visit 1 OR
   • ≥1 tendon friction rub

7. Elevated biomarkers on Visit 1 (screening) defined as at least one of the following:

   • C-reactive protein (CRP) ≥6 mg/L (≥0.6 mg/dL), OR
   • Erythrocyte sedimentation rate (ESR) ≥28 mm/h, OR
   • Krebs von den Lungen 6 (KL-6) ≥1000 U/mL If none of the three criteria are met or respective test results should not be available, the patient can be entered if the modified Disease Activity Index (mDAI) is ≥ 2.5.

8. Evidence of significant vasculopathy, defined as:

   • Active Digital ulcer (DU(s)) on Visit 1 OR
   • Documented history of DU(s), OR
   • Previous treatment of RP with prostacyclin analogues or ≥ 1 other medications, including calcium channel blockers, nitrates,, NO donors in any form, including topical; phosphodiesterase 5 (PDE5) inhibitors (e.g. sildenafil, tadalafil, vardenafil); nonspecific PDE5 inhibitors (theophylline, dipyridamole) OR
   • RP with elevated CRP ≥6 mg/L
   • If none of the four criteria above are met, the patient can be entered if the diagnosis of Interstitial lung disease (ILD) has been confirmed Further inclusion criteria apply.

Exclusion Criteria:

1. Any known form of pulmonary hypertension.
2. Pulmonary disease with FVC <50% of predicted. at screening.
3. Other autoimmune connective tissue diseases, except for fibromyalgia, scleroderma-associated myopathy and secondary Sjogren syndrome.
4. Diffusing capacity for carbon monoxide (DLCO) (haemoglobin corrected) <40% of predicted at screening.
5. Any history of scleroderma renal crisis within the last 6 months.
6. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology (CKD-EPI) formula) or on dialysis at screening.
7. Cirrhosis of any Child-Pugh class (A, B or C).
8. Cholestasis at present, or Alkaline phosphatase (ALP) > 4 x Upper limit of normal (ULN), or ALP > 2 x ULN and Gamma-glutamyl transferase (GGT) > 3 x ULN at Screening.

Further exclusion criteria apply.