#230 INShore: phase III, multicentre, randomised, open-label study of efficacy and safety of obinutuzumab vs MMF in patients with childhood-onset idiopathic nephrotic syndrome

Abstract Background and Aims Patients with childhood-onset frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) need approved therapies that sustain clinical remission and minimise glucocorticoid burden. Over the past decade, the effectiveness of B-cell–depleting monoclonal antibodies, primarily rituximab, for treating FRNS/SDNS has established the pathogenic role of B cells in this condition. Obinutuzumab, a type II anti-CD20 monoclonal antibody, depletes B cells more effectively than rituximab. The INShore study (NCT05627557, EU CT 2023-505140-19-00) assesses the efficacy and safety of obinutuzumab versus mycophenolate mofetil (MMF) among children and young adults (aged ≥2–25 years) with childhood-onset FRNS or SDNS. Method Participants in complete remission but at high risk of relapse are randomly assigned in a 1:1 ratio to receive obinutuzumab or MMF (Fig. 1). Intravenous obinutuzumab (1000 mg or 20 mg/kg for participants <45 kg) is infused on Day 1 and Weeks 2, 24 and 26; MMF (titrated by Week 4 to 1200 mg/m2/day) is given orally twice daily until Week 52, after which administration must be discontinued or tapered over the subsequent 3 months. Participants in either arm receiving oral glucocorticoids at randomisation follow a guided taper to achieve a target of 0 mg by Week 8. Participants and/or their caregivers assess urine protein via dipstick daily home monitoring. Relapse is confirmed by first morning void urine protein-to-creatinine ratio (UPCR) laboratory testing and is defined as: (1) UPCR ≥2 g/g, (2) dipstick urinalysis protein ≥3 for 3 consecutive days with the most recent UPCR >0.2 g/g or 3) dipstick urinalysis protein ≥3 on any single day with oedema and UPCR >0.2 g/g. The primary endpoint is the proportion of participants with sustained complete remission at 1 year, defined as first morning void UPCR ≤0.2 g/g at Week 52. Secondary endpoints include overall relapse-free survival, cumulative glucocorticoid dose, number of relapses and proportion of participants with sustained, complete remission at Week 76. Results INShore is fully enrolled with 85 participants across 32 sites and 9 countries. The study population comprises 30 (35.3%) females and 55 (64.7%) males; 23 (27.1%) Asian participants, 14 (16.5%) Black or African American participants, 47 (55.3%) white participants and 1 (1.2%) participant whose race is unknown; 38 (44.7%) have FRNS and 47 (55.3%) SDNS; 50 (58.8%) received prior non-steroid immunosuppressive therapy for the treatment of FRNS/SDNS. At baseline, mean (SD) age was 9.9 (4.39) years and serum albumin was 4.3 (0.42) g/dl; median [IQR] estimated glomerular filtration rate was 120.0 [110.0, 134.0] ml/min/1.73 m2 and UPCR was 0.0 [0.0, 0.1] g/g. Conclusion The successful enrolment and diverse demographics of the INShore study participants provide a robust basis for assessing the efficacy and safety of obinutuzumab versus MMF in managing childhood-onset idiopathic nephrotic syndrome. Full results of the INShore study will be available following the primary analysis, once all participants have completed 52 weeks in the study.