A Phase 2 Trial of Frexalimab, a <scp>CD40L</scp> Antagonist, in Adolescents and Adults With Recent‐Onset Type 1 Diabetes ( <scp>FABULINUS</scp> ): Rationale and Study Design

INTRODUCTION: Type 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing pancreatic β-cells. Preserving remaining β-cells at the time of diagnosis may improve long-term outcomes. Frexalimab is a humanised monoclonal antibody specific for CD40L undergoing evaluation for treatment of various immune-mediated conditions. METHODS AND ANALYSIS: This is a double-blind, Phase 2 trial to assess the efficacy and safety of frexalimab for preservation of pancreatic β-cell function in adolescents and young adults (12-35 years) with recently diagnosed Stage 3 T1D on insulin therapy. Participants who meet all inclusion criteria will be randomly assigned to receive frexalimab or a matching placebo in a 2:1 ratio in all cohorts for 104 weeks. A total of 192 participants will be recruited sequentially into two parts. Part A (n = 30) is exploratory and designed to establish the safety of the highest dose of frexalimab compared with placebo in adults (18-35 years). In Part B, 162 adolescents and young adults (12-21 years) are randomised sequentially to three age-adjusted dose-levels of frexalimab or placebo. The primary endpoint is the change from baseline to 52 weeks in mean 2-h mixed meal tolerance test stimulated C-peptide concentration, calculated from the area under the curve. Secondary endpoints include time in range by intermittent continuous glucose monitoring measures, glycated haemoglobin (HbA1c), daily insulin dose, number of hypoglycaemic events and insulin dose adjusted HbA1c measurements. ETHICS AND DISSEMINATION: This trial received ethical approval in October 2023 and began screening in December 2023 with first participant randomised in January 2024. The results will be submitted to a peer-reviewed medical journal and presented at conferences. TRIAL REGISTRATION: EU trial number: 2022-500531-36-00 and ClinicalTrials.gov: NCT06111586.