Phase 3 Randomized Double-Blind Trial of Rituximab and Subcutaneous Belimumab Versus Rituximab and Placebo in Adults with Chronic Immune Thrombocytopenia

The primary objective of this study is to evaluate the **superiority** of a combination of subcutaneous belimumab administered weekly over a 24-week period (Arm A) compared to a subcutaneous placebo administered weekly over the same period (Arm B), both in conjunction with rituximab (or its biosimilar) at a fixed dose of 1,000 mg on Day 7 and Day 21, in adult patients with persistent or chronic immune thrombocytopenia (ITP). This assessment is conducted at Week 52. The clinical relevance of this objective lies in determining the efficacy and safety of the combination therapy in improving patient outcomes in ITP, a condition characterized by low platelet counts and increased risk of bleeding.

Secondary objectives include: - Analyzing the overall response (complete response + response) of patients throughout the study until Week 104. - Assessing the incidence of secondary hypogammaglobulinemia (<4 g/dl) in both arms at Weeks 12, 24, 36, 52, 78, and 104. - Evaluating levels of gammaglobulin classes and subclasses over the course of the study period. - Comparing the number of severe infections (requiring hospitalization) in both arms over the study period. - Assessing hemorrhagic events occurring throughout the study. - Comparing the rate and type of anti-platelet antibodies in both arms at baseline, Week 24, Week 52, and Week 104. - Assessing patients' quality of life at inclusion, Week 24, and Week 52. - Analyzing changes in B-cell subpopulations in peripheral blood under treatment and during B-cell reconstitution, as well as BAFF and pro-inflammatory cytokines, and changes in T-CD4+ helper follicular subsets at specified time points.

The clinical trial involves **adult patients** diagnosed with persistent or chronic **immune thrombocytopenia**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a history of primary immune thrombocytopenia (ITP) with a previous transient response to first-line treatments such as corticosteroids or intravenous immunoglobulin (IgIV). The trial does not include a vulnerable population. Participants must have a platelet count of ≤ 30 x 10⁹/L within the previous month or <50 x 10⁹/L if there are hemorrhagic events or other reasons as determined by the investigator. The duration of ITP should be more than 2 months but less than 10 years from diagnosis. For those over 60 years, a normal bone marrow smear is required. Female participants of childbearing potential must have a negative pregnancy test and use effective contraception. All participants must have completed a vaccination scheme against SARS-CoV-2 as per health authority recommendations and have a gammaglobulin level of ≥ 7 g/L. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of rituximab combined with subcutaneous **belimumab** versus rituximab plus placebo in adult patients with persistent or chronic **immune thrombocytopenia** (ITP). The trial is structured to assess the superiority of the combination treatment over a 24-week period, with the primary endpoint being the overall response rate at week 52. The study is expected to run from November 2022 to November 2027, with participant involvement lasting up to 104 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, informed consent, and specific medical conditions. Following the screening, participants will be randomized into one of two arms: Arm A receiving subcutaneous belimumab weekly, or Arm B receiving a placebo, both in combination with rituximab. The trial includes follow-up visits at weeks 6, 12, 24, 36, 52, 78, and 104 to monitor response rates, platelet levels, and other health indicators. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse events.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include severe adverse reactions, withdrawal of consent, or non-compliance with study protocols. The trial's design ensures rigorous monitoring and data collection to evaluate both primary and secondary endpoints, including the duration of severe hypogammaglobulinemia, number of severe infections, and quality of life assessments using standardized questionnaires. The study aims to provide comprehensive data on the therapeutic potential of belimumab in combination with rituximab for treating ITP.

The clinical trial involves the administration of **Benlysta**, a **200 mg solution for injection** in a pre-filled pen, containing the active substance **belimumab**. This pharmaceutical form is designed for **subcutaneous administration**. The dosing regimen for Benlysta involves a maximum daily dose of 200 mg, with a total maximum dose of 4800 mg over the treatment period. The treatment is administered weekly for a duration of 24 weeks. The product is supplied in bulk form without labels, and participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule. The active substance, belimumab, is a protein of other origin, and the product is manufactured by GlaxoSmithKline (Ireland) Limited.

The study also includes a **placebo** comparator, referred to as the **Placebo of Belimumab**. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner and frequency as the active treatment, providing a control for evaluating the efficacy and safety of the experimental medication. The placebo does not contain any active substance and is used to assess the superiority of the combination treatment involving belimumab.

Efficacy in the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the overall response rate, defined as the sum of complete responses (CR) and responses (R) in both treatment arms at week 52 (W52). Secondary endpoints include the total number of responders at various timepoints (W6, W12, W24, W36, W52, W78, W104), the duration and incidence of severe **hypogammaglobulinemia**, and variations in gammaglobulin classes and subclass levels throughout the study. Additional secondary endpoints involve the number of severe infections requiring hospitalization, the number of hemorrhagic events evaluated by the Khellaf Score, and platelet levels at specified weeks. Patient quality of life will be assessed using the SF-36 health questionnaire and the FACIT-Fatigue scale at inclusion, W12, W24, and W52. The study will also measure the percentage of each B-cell subpopulation, T Follicular helper population, and levels of cytokines, including BAFF, and anti-platelet antibodies at designated timepoints.