Efficacy and Safety of Obinutuzumab Versus Glucocorticoid Therapy in Adults with De Novo Minimal Change Disease: A Phase IIa Randomized Controlled Trial

The primary objective is to evaluate the efficacy of obinutuzumab compared to the standard of care, consisting of a progressive 24-week oral glucocorticoid therapy, in the management of adults with newly onset biopsy-proven minimal change disease. This comparison aims to establish both non-inferiority and superiority of the investigational treatment. Secondary objectives include:

• Assessment of time to remission and time to disease relapse.
• Evaluation of patient-reported health-related quality of life and glucocorticoid toxicity.
• Comparison of safety profiles between treatment arms.
• Investigation of general risk factors as potential predictors of relapse.
• Exploration of experimental biomarkers to predict treatment response, sustained remission, relapse, and specific side effects.

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients aged 18 years or older with newly onset, biopsy-proven minimal change disease. Eligible participants must have a confirmed first episode of nephrotic syndrome, characterized by a serum albumin level below 30g/l and a urine protein-to-creatinine ratio greater than 3g/g creatinine. For women of childbearing potential, a negative pregnancy test is required, alongside agreement to follow specific contraceptive guidance. The study population includes vulnerable individuals.

This Phase IIa, randomized, controlled, two-arm trial utilizes a 1:1 ratio to evaluate the efficacy and safety of obinutuzumab compared to a standard of care involving an oral glucocorticoid therapy regimen that is progressively tapered over 24 weeks. The study is designed for adults with de novo minimal change disease, characterized by a first episode of nephrotic syndrome and histological confirmation. Following a screening visit to confirm eligibility through criteria such as serum albumin levels and urinary protein-to-creatinine ratio, participants are assigned to either the test or comparator arm. The primary objectives involve assessing the non-inferiority of obinutuzumab at 8 weeks and its superiority in sustaining remission or preventing relapse over a 52-week study period. Throughout the clinical course, secondary endpoints include measurements of kidney function, glomerular filtration rate, and various safety parameters. The total duration of participant involvement is expected to be 52 weeks.

The investigational product is obinutuzumab, provided as a 1,000 mg concentrate for solution for infusion. This medication is administered via intravenous infusion.

The comparator treatment consists of an oral glucocorticoid regimen. This includes either prednisolone or betamethasone sodium phosphate, both administered at a dose of 80 mg via the oral route. This standard-of-care therapy is subject to a progressive taper over 24 weeks.

Auxiliary medications utilized in the study include rituximab, administered as a 1,000 mg intravenous infusion, and tacrolimus, administered at a dose of 0.5 mg via the oral route.

The primary efficacy assessment evaluates the non-inferiority of obinutuzumab compared to a standard of care glucocorticoid taper by measuring the proportions of patients achieving remission, including both complete or partial states, of minimal change disease at 8 weeks. Superiority is assessed by the proportions of patients sustaining remission or preventing relapse throughout a 52-week study period.

Secondary efficacy parameters include:

• Time to complete remission, partial remission, or disease relapse.
• Changes in the Glucocorticoid Toxicity Index from baseline to day 60, week 26, and week 52.
• Changes in the urinary protein-to-creatinine ratio, albumin-to-creatinine ratio, and serum albumin from baseline to week 26 and week 52.
• Changes in kidney function measured by the 2021 race-free CKD-EPI estimated glomerular filtration rate from baseline to week 26 and week 52.
• Patient-reported health-related quality of life assessed via the EuroQol 5-Dimensions 5-Levels Questionnaire.

Exploratory assessments involve the sequential measurement of anti-nephrin antibodies, identification of B and T cell subsets, and the evaluation of anti-obinutuzumab antibodies. Further exploratory analyses include single cell RNA sequencing signatures and the identification of differentially expressed proteins or lipids through plasma/PBMC proteomics and plasma lipidomics.