A Randomized, Double‑Blind, Placebo‑Controlled Trial of Oral Nerandomilast (BI 1015550) in Patients with Systemic Sclerosis

The primary objective of the double‑blind, randomized, placebo‑controlled trial in patients with systemic sclerosis is to demonstrate the superiority of nerandomilast over placebo for the hazard ratio of the composite endpoint of all‑cause death or disease progression, reflecting overall survival and disease worsening. Secondary objectives include:

• Mean change from baseline in modified Rodnan skin score (mRSS) at Week 52.
• Mean change from baseline in Health Assessment Questionnaire Disability Index (HAQ‑DI) at Week 52.
• Mean change from baseline in forced vital capacity (FVC) in milliliters at Week 52.
• Difference in response rate for the revised composite response index (rCRISS‑25) at Week 52.
• Hazard ratio for time to each individual component of the primary composite endpoint.
• Mean change from baseline in Systemic Sclerosis Impact of Disease (ScleroID) at Week 52.
• Mean change from baseline in total digital ulcer burden at Week 52.

A total of 269 participants with systemic sclerosis were enrolled. Both male and female adults aged 18 years and older were included. Eligible individuals met the 2013 ACR/EULAR classification criteria and had either limited cutaneous or diffuse cutaneous disease as defined by LeRoy et al., with disease onset within seven years of screening. Baseline pulmonary function required forced vital capacity ≥45 % predicted and diffusing capacity for carbon monoxide ≥25 % predicted. Participants could be treatment‑naïve or receiving stable doses of permitted immunosuppressive or immunomodulatory agents, including nintedanib, throughout the screening period. Women of childbearing potential were required to use highly effective contraception. The cohort comprised patients with active disease at screening, consistent with the trial’s focus on disease progression.

The study is a double‑blind, randomized, placebo‑controlled trial evaluating oral nerandomilast in adult participants with systemic sclerosis. Participants are allocated 1:1 to receive either nerandomilast 36 mg, nerandomilast 18 mg, or matching placebo, administered once daily. The trial duration is approximately 48 weeks of treatment plus a follow‑up period, with total study involvement of about 52 weeks per participant. After signed informed consent, a screening visit confirms eligibility criteria, baseline assessments, and stability of concomitant immunosuppressive therapy. Eligible participants attend a baseline (Visit 2) where randomization occurs and study medication is dispensed. Subsequent visits are scheduled at Weeks 4, 12, 24, 36, and 52 to assess safety, efficacy endpoints, and adherence; the primary endpoint is time to first disease progression or all‑cause death, expressed as a hazard ratio. An end‑of‑study visit at Week 52 (or earlier if premature discontinuation occurs) includes final efficacy assessments and safety evaluations. Participants may be withdrawn early for predefined reasons such as protocol non‑compliance, emergence of prohibited concomitant therapy, serious adverse events, or investigator‑determined lack of benefit. Recruitment began in June 2026 and the study is planned to conclude in March 2030.

The investigational product, identified as nerandomilast (BI 1015550), is supplied as a film‑coated tablet for oral administration. Each tablet contains 36 mg of the active substance and is taken once daily throughout the treatment period.

A second dosage strength of the same investigational product is provided as a film‑coated tablet containing 18 mg of BI 1015550, also administered orally once daily for the duration of the study.

Matching placebo tablets, identical in size, weight, colour, and shape to the active tablets, are administered orally once daily on the same schedule as the active arms to maintain blinding.

All study medications are dispensed in blister packs, and participants receive dosing instructions at each study visit. Compliance is monitored by tablet count, patient diaries, and electronic case report forms to ensure adherence to the prescribed regimen.

Efficacy will be evaluated primarily by the time to the first occurrence of disease progression or all‑cause death, analyzed using time‑to‑event statistical methods. Secondary efficacy parameters include the change from baseline to Week 52 in the modified Rodnan Skin Score (mRSS), the Health Assessment Questionnaire‑Disability Index (HAQ‑DI), forced vital capacity measured in millilitres (forced vital capacity (FVC)), the Systemic Sclerosis Impact of Disease (ScleroID) score, and the total burden of digital ulcers. Disease improvement will also be assessed at Week 52 using the rCRISS‑25 composite response index. Additional time‑to‑event secondary endpoints comprise confirmed absolute decline in FVC % predicted ≥5 % (or new interstitial lung disease), absolute increase in mRSS ≥5 points and ≥25 % relative increase, adjudicated SSc‑related clinically meaningful disease progression, and all‑cause death.

Assessments will be performed at baseline and at Week 52 for the change‑from‑baseline endpoints, employing validated clinical scoring tools for mRSS, standardized questionnaires for HAQ‑DI and ScleroID, spirometric measurement for FVC, and documented counts for digital ulcer burden. Time‑to‑event outcomes will be captured continuously throughout the treatment period up to the end of the study, with events recorded at each scheduled visit and analyzed using appropriate survival analysis techniques.