Rituximab-Based Memory B Cell Level-Guided Therapy in Pediatric Complicated Steroid-Sensitive Nephrotic Syndrome: A Randomized Controlled Trial

The primary objective of the MEMORINEPH study is to define the optimal number of **rituximab** (RTX) re-infusions in children with complicated forms of frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). This is achieved through an open-label randomized controlled trial comparing two different regimens for repeated RTX treatment based on the reconstitution of total B cells (Arm A) or memory B cells (Arm B). The clinical relevance of this objective lies in optimizing treatment strategies to reduce the frequency of relapses and improve patient outcomes in this pediatric population.

Secondary objectives include evaluating the impact of the two different retreatment regimens with RTX on the number of relapses, days of hospitalization required, and severe infections. Additionally, exploratory aims involve assessing the effects on humoral immunity and the potential onset of anti-RTX antibodies by comparing the two different repeated RTX treatment regimens (A vs B).

The clinical trial involves participants diagnosed with **complicated forms of idiopathic steroid-sensitive nephrotic syndrome (SSNS)**. The study population includes both male and female subjects, ranging in age from 3 to 24 years. Participants are children and young adults who experience at least two relapses per year while on mycophenolate mofetil and/or a calcineurin inhibitor at appropriate doses. The trial population was selected based on their medical condition and treatment history, with previous infusions of RTX being permissible. The study includes a vulnerable population, as it involves pediatric patients. The sponsor has not provided the total number of participants. Participants are required to use a reliable contraceptive method if they have reproductive potential. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the optimal number of **rituximab** re-infusions in children with complicated forms of idiopathic steroid-sensitive nephrotic syndrome (SSNS). This is an open-label, randomized, controlled trial comparing two different regimens for repeated rituximab treatment based on the reconstitution of total B cells (Arm A) or memory B cells (Arm B). The trial is categorized as a Phase 4 study and is not considered low intervention. The trial is expected to commence recruitment on November 1, 2024, and conclude by June 1, 2028, with a total duration of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age (3 to 24 years) and history of relapses while on mycophenolate mofetil or a calcineurin inhibitor. Informed consent will be obtained from adult participants or the parents/legal guardians of pediatric participants, with assent from adolescent and school-aged participants. The primary endpoint is the evaluation of the number of rituximab re-infusions required, assessed through flow cytometry of B cell reconstitution over the 24-month follow-up period. Secondary endpoints include the number of relapses, hospitalization days, severe infections, and time to first relapse, along with exploratory assessments of immunoglobulin levels and antibody titers.

Participants will be involved in the study for a maximum of 104 weeks, with regular follow-up visits to monitor treatment efficacy and safety. Conditions that may lead to early termination from the study include the inability to comply with study procedures or the occurrence of adverse events that necessitate withdrawal. The study will utilize Rixathon, a concentrate for solution for infusion, with a maximum daily dose of 1000 mg and a total dose not exceeding 4000 mg. The trial aims to provide insights into the tailored treatment of SSNS, potentially improving patient outcomes through personalized therapy regimens.

The clinical trial involves the administration of **Rixathon**, a **rituximab**-based medication, which is a **concentrate for solution for infusion**. Rixathon is available in two dosages: 500 mg and 100 mg. The pharmaceutical form for both dosages is a solution for infusion, and the route of administration is intravenous infusion. The maximum daily dose is 1000 mg, with a total maximum dose of 4000 mg over the treatment period. The treatment period is set to a maximum of 104 weeks. The active substance, rituximab, is a protein of non-human origin, specifically classified under the ATC code L01FA01. The product is manufactured by Sandoz GmbH and is authorized for use in the European Union.

In this study, Rixathon is used to treat children with complicated forms of steroid-sensitive nephrotic syndrome. The trial aims to determine the optimal number of rituximab re-infusions by comparing two different regimens based on the reconstitution of total B cells or memory B cells. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance is monitored through regular assessments of B cell levels to guide the administration schedule. The study is designed to ensure that the administration of rituximab is tailored to the individual needs of the participants, based on their B cell reconstitution status.

Efficacy in the clinical trial will be assessed through a series of primary and secondary endpoints over a 24-month follow-up period. The primary endpoint involves evaluating the number of **rituximab** (RTX) re-infusions by comparing two therapeutic regimens based on flow cytometry assessment of total B cell reconstitution (Arm A) or memory B cells (Arm B). This assessment aims to determine the optimal number of RTX re-infusions in children with complicated forms of steroid-sensitive nephrotic syndrome.

Secondary endpoints include the assessment of the number of relapses, defined by the reappearance of massive proteinuria or a positive urine dipstick, with or without edema. Additional secondary endpoints are the number of hospitalization days, the number of severe infections requiring hospitalization, and the time to the first relapse or a positive urine dipstick. Exploratory endpoints will involve evaluating serum levels of total immunoglobulins IgG, IgM, and IgA, as well as antibody titers specific to tetanus and HBV induced by vaccination, using immunoturbidimetry and ELISA tests. The incidence of prolonged hypogammaglobulinemia and/or severe hypogammaglobulinemia will also be assessed, with a potential need for the introduction of replacement therapy with IgG.