A phase 2b basket trial approach to treat multiple rare and fibrotic skin diseases

Sebastian Volc^1,2*Peter Martus³Matthias Schefzyk⁴Claudia Günther^2,5Pia Moinzadeh⁶Laura Susok⁷Rubén A Ferrer⁸Manola Zago⁹Christiane Pfeiffer⁸

• ¹University Hospital and Faculty of Medicine, University of Tübingen, Tübingen, Germany
• ²Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
• ³Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard Karls University, Tuebingen, Germany
• ⁴Medizinische Hochschule Hannover Klinikum Klinik fur Dermatologie Allergologie und Venerologie, Hanover, Germany
• ⁵Department of Dermatology, University Hospital, Medizinische Fakultät Carl Gustav Carus, TU Dresden, Dresden, Germany
• ⁶Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
• ⁷Department of Dermatology, Klinikum Dortmund gGmbH, University Witten/Herdecke, Dortmund, Germany
• ⁸Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
• ⁹Center for Clinical Trials, University Hospital of Tuebingen, Tuebingen, Germany

Fibrotic skin diseases are rare, chronic, and often debilitating conditions characterized by excessive extracellular matrix deposition, leading to tissue scarring and functional impairment. Despite their severity, diseases-such as lichen sclerosus et atrophicus (LSA), frontal fibrosing alopecia (FFA), radiation-induced skin fibrosis (RISF), eosinophilic fasciitis (EF), pansclerotic disabling morphea (PDM), and linear circumscript sclerodermia (LCS)-lack approved therapies and are underrepresented in clinical research. This phase 2b multicenter basket trial proposes a novel approach to evaluate a common antifibrotic therapy across these diverse but pathophysiologically related conditions.The trial employs a two-stage Simon design to address the statistical challenges posed by small patient populations, allowing inclusion of ultra-rare diseases while maintaining analytical rigor. LSA and FFA serve as primary study groups due to higher prevalence, while EF, RISF, PDM, and LCS are included as exploratory arms. The study aims to assess efficacy, safety, and tolerability of the selected therapy, alongside mechanistic insights into fibrosis through molecular analyses.The Primary primary endpoints include is a ≥ 21-point improvement in the Investigator Global Assessment (IGA) at 24 weeks. Secondary endpoints at 52 weeks encompass quality of life (DLQI, EQ-5D), symptom relief (itch and pain NRS), and disease-specific clinical scores. The trial excludes a placebo arm due to ethical considerations in progressive, untreated diseases, but allows rescue therapies for disease progression. This design not only facilitates access to treatment for underserved populations but also leverages shared clinical and molecular features to enhance statistical power. By integrating disease-specific and global outcome measures, the study aims to generate robust evidence for repurposing existing therapies. If successful, this trial could serve as a model for future research in rare fibrotic diseases, accelerating drug development and improving patient outcomes.