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

The primary objective of this study is to evaluate the **superiority** of BI 685509 over placebo by assessing the mean difference in the annual rate of decline in Forced Vital Capacity (FVC) over a period of 48 weeks in patients with progressive systemic sclerosis. This objective is clinically relevant as it aims to determine the potential of BI 685509 in slowing the progression of lung function decline, a critical concern in systemic sclerosis management.

Secondary objectives include:

• Assessing the superiority of BI 685509 over placebo for absolute change from baseline in the modified Rodnan skin score (mRSS).
• Evaluating the digital ulcer (DU) net burden at Week 48, American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) scores, proportions of responders based on the revised CRISS, and time to treatment failure at Week 48.
• Measuring FVC as a percentage of predicted values.
• Conducting patient and physician global assessments.
• Assessing Health Assessment Questionnaire-Disability Index (HAQ-DI) and Raynaud's Phenomenon (RP) activity.

The clinical trial involves a total of **131 participants** diagnosed with **systemic sclerosis**. The study population includes both male and female patients aged 18 years and older, with no vulnerable populations selected. Participants were required to provide signed and dated written informed consent in accordance with ICH-GCP and local legislation. The trial population was selected based on the fulfillment of the 2013 ACR/EULAR classification criteria for systemic sclerosis, with patients having either limited or diffuse cutaneous forms of the disease. The onset of diffuse cutaneous systemic sclerosis must be within 7 years, and limited cutaneous systemic sclerosis within 2 years of the initial visit. Participants were also required to show evidence of active disease or significant vasculopathy. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure a focus on individuals with active disease progression, as indicated by specific clinical and biomarker assessments.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy and safety of the investigational drug BI 685509 in adults with **systemic sclerosis**. The trial will span a duration of at least 48 weeks, with the primary objective being to assess the superiority of BI 685509 over placebo based on the mean difference in the annual rate of decline in forced vital capacity (FVC). The study will include multiple visits, starting with an inclusion (screening) visit, followed by regular follow-up visits, and concluding with an end-of-study visit. Participants will be involved in the study for the entire 48-week period unless early termination is warranted due to adverse events, non-compliance, or withdrawal of consent.

During the screening visit, eligibility will be confirmed based on criteria such as age, diagnosis of systemic sclerosis, and evidence of active disease. Follow-up visits will be conducted to monitor the participants' health, assess the primary and secondary endpoints, and ensure adherence to the study protocol. The primary endpoint is the rate of decline in FVC over 48 weeks, while secondary endpoints include changes in modified Rodnan skin score (mRSS), Health Assessment Questionnaire-Disability Index (HAQ-DI) score, and other systemic sclerosis-related measures. The end-of-study visit will involve a comprehensive evaluation of the participants' health status and the collection of final data for analysis.

Participants are expected to adhere to the study protocol, including the administration of the investigational drug or placebo in the form of **film-coated tablets** taken orally. The maximum daily dose of BI 685509 is set at 9 mg, with a total dose not exceeding 4158 mg over the treatment period. Conditions that may lead to early termination from the study include significant adverse events, failure to comply with the study protocol, or voluntary withdrawal by the participant. The trial aims to provide valuable insights into the potential benefits of BI 685509 in managing systemic sclerosis, contributing to the development of effective treatment strategies for this condition.

The clinical trial involves the administration of **BI 685509**, an investigational medication developed by Boehringer Ingelheim International. **BI 685509** is provided in the form of a **film-coated tablet** and is administered orally. The trial includes three different dosing regimens of **BI 685509**. The first regimen involves a maximum daily dose of 9 mg, with a total maximum dose of 4158 mg over a treatment period of 462 days. The second regimen allows for a maximum daily dose of 3 mg, with a total maximum dose of 1470 mg over a treatment period of 70 days. The third regimen permits a maximum daily dose of 6 mg, with a total maximum dose of 2856 mg over a treatment period of 68 days. The active substance in all regimens is of chemical origin, and the medication is not formulated for pediatric use.

In addition to the experimental medication, the study includes a **placebo** group. The placebo is designed to match the **film-coated tablet** form of **BI 685509** and is also administered orally. The placebo serves as a comparator to evaluate the efficacy and safety of **BI 685509** in the treatment of progressive systemic sclerosis. The use of a placebo allows for a double-blind, randomized, and controlled study design, ensuring that the effects observed can be attributed to the investigational medication.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial aims to assess the superiority of **BI 685509** over placebo by evaluating the mean difference in the annual rate of decline in forced vital capacity (FVC) over a period of 48 weeks. The study employs a treatment policy strategy, considering the effects of any changes in treatment among all randomized patients.

The efficacy of the investigational product **BI 685509** in the treatment of progressive systemic sclerosis will be assessed through a series of predefined endpoints over a 48-week period. The primary endpoint is the rate of decline in forced vital capacity (FVC) measured in milliliters over the course of the study. This will be used to determine the superiority of **BI 685509** over placebo. Secondary endpoints include the absolute change from baseline in the modified Rodnan skin score (mRSS) at Week 48 for participants with diffuse cutaneous systemic sclerosis (dcSSc), and the proportion of responders based on the revised CRISS criteria at Week 48. Additional secondary endpoints involve changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, ACR-CRISS score, and various other clinical measures such as the Physician Global Assessment (PGA) and the Composite measure of Raynaud's Phenomenon (RP) activity.

Data collection will occur at baseline and at the 48-week mark, with specific assessments conducted using validated scales and clinical evaluations. The analysis will include all randomized patients, employing a treatment policy strategy to account for any changes in treatment during the trial. The efficacy assessments will be conducted in a double-blind, placebo-controlled manner to ensure the reliability and validity of the results. The trial is designed to provide comprehensive data on the efficacy of **BI 685509** in improving clinical outcomes for patients with progressive systemic sclerosis.