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

Study Overview
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Brief Summary
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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 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 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.

Official Title
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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

Conditions
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Scleroderma, Systemic

Intervention / Treatment
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* Drug: BI 685509
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Male or female patients aged ≥18 years at time of consent (or above legal age, e.g. United Kingdom (UK) ≥16 years). Patients must fulfill the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for Systemic sclerosis (SSc). 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. 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. 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 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. 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: Any known form of pulmonary hypertension. Pulmonary disease with FVC <50% of predicted. at screening. Other autoimmune connective tissue diseases, except for fibromyalgia, scleroderma-associated myopathy and secondary Sjogren syndrome. Diffusing capacity for carbon monoxide (DLCO) (haemoglobin corrected) <40% of predicted at screening. Any history of scleroderma renal crisis within the last 6 months. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology (CKD-EPI) formula) or on dialysis at screening. Cirrhosis of any Child-Pugh class (A, B or C). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 685509<br>BI 685509 | Drug: BI 685509<br>* BI 685509<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of decline in forced vital capacity (FVC) (mL) over 48 weeks |  | 48 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change from baseline in Modified Rodnan Skin Score (mRSS) at Week 48 in study participants with diffuse cutaneous systemic sclerosis (dcSSc) | To measure mRSS, skin thickness of the patient is rated by palpation using a scale of 0-3, with 0 = normal skin; 1= mild thickness; 2= moderate thickness and 3=severe thickness with an inability to pinch the skin into a fold (worst outcome). | At baseline and at week 48. | 
| Proportion of responders in study participants with diffuse cutaneous systemic sclerosis (dcSSc) based on the revised Composite Response Index in Systemic Sclerosis (CRISS) at Week 48 | Revised Composite Response Index in Systemic Sclerosis (CRISS) at Week 48 (Achievement of ≥ 20% improvement from baseline to week 48 in at least 3 of the 5 core set measures, except ≥ 5% in Forced Vital Capacity (FVC) percent predicted). The CRISS is a two-step composite index which includes in Step 2 the mRSS, FVC percent predicted, HAQ-DI, patient's global assessment and clinicians's global assessment. Step 1 in the ACR-CRISS version consists of the absence of significant worsening of interstitial lung disease, a new scleroderma renal crisis, left ventricular failure or pulmonary arterial hypertension. The revised version proposes that the absence of significant gastrointestinal dysmotility requiring parenteral or enteral nutrition and significant digital ischaemia requiring hospitalisation, gangrene or amputation are added to Step 1. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A higher score indicates greater improvement. | At baseline and at week 48. | 
| Absolute change from baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) score at Week 48 | HAQ-DI; 20-question instrument assessing 8 functional areas; range: 0-3, 0= no difficulty, 3= inability to perform task in that area. | At baseline and at week 48. | 
| American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) score in study participants with diffuse cutaneous systemic sclerosis (dcSSc) at Week 48 | The CRISS is a two-step composite index which includes in Step 2 the Modified Rodnan Skin Score (mRSS), FVC percent predicted, Health Assessment Questionnaire - Disability Index (HAQ-DI), patient's global assessment and clinicians's global assessment. Step 1 in the ACR-CRISS version consists of the absence of significant worsening of interstitial lung disease, a new scleroderma renal crisis, left ventricular failure or pulmonary arterial hypertension. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A higher score indicates greater improvement. | At week 48. | 
| Absolute change from baseline in forced vital capacity (FVC) (mL) at Week 48 |  | At week 48. | 
| Absolute change from baseline in forced vital capacity (FVC) (% predicted) at Week 48 |  | At baseline and at week 48. | 
| Absolute change from baseline in the Patient Global Assesment (PGA) Visual Analog Scale (VAS) score at Week 48 | The PGA is a self-assessment on the patient's overall health in the prior 1 week using a 0-10 ordinal scale, with a higher score indicating a worse outcome. | At baseline and at week 48. | 
| Absolute change from baseline in the Clinician Global Assessment (CGA) Visual Analog Scale (VAS) score at Week 48 | Clinician assessment (CGA) on the patient's overall health in the prior 1 week using a 0-10 ordinal scale, with a higher score indicating a worst outcome. | At baseline and at week 48. | 
| Composite measure of Raynaud's phenomenon (RP) activity at Week 48 |  | Week 48. | 
| Absolute change from baseline in Digital ulcer (DU) net burden at Week 48 |  | At baseline and at week 48. | 
| Time to treatment failure | Time to treatment failure, defined as the time to one of the following events (whichever occurs first) occurring over the 48-week and extended treatment period: death, absolute decline in percent-predicted forced vital capacity (FVC) ≥10% relative to baseline, ≥25% increase in Modified Rodnan Skin Score (mRSS) and an increase in mRSS of >5 points, initiation or dose change of immunomodulating/immunosuppressive therapy for clinically significant deterioration of Diffuse cutaneous systemic sclerosis (dcSSc) | 48 weeks. | 
| Time to Modified Rodnan Skin Score (mRSS) progression (≥25% increase in mRSS and an increase in mRSS of >5 points) in study participants with diffuse cutaneous systemic sclerosis (dcSSc) |  | 48 weeks. | 
| Proportion of study participants with diffuse cutaneous systemic sclerosis (dcSSc) with Modified Rodnan Skin Score (mRSS) progression (25% increase in mRSS and an increase in mRSS of >5 points) |  | 48 weeks. |