Primary immune thrombocytopenia (ITP) is an autoimmune disease mainly mediated by autoreactive B cells and the presence of pathogenic anti-platelet auto-antibodies that enhance platelet destruction and impair platelet production. There are approximately 4,000 newly diagnosed ITP cases each year in France. For patients with a platelet count of less than 30x109/L and/or bleeding symptoms, corticosteroids alone or in combination with intravenous immunoglobulin (IVIg) is the standard first-line treatment. However, approximately two-thirds of adult patients responding to this first-line treatment relapse within days or weeks after corticosteroids withdrawal and overall, the course of the disease is chronic in about 70% of the cases. The anti-CD20 monoclonal antibody rituximab is commonly used off-label as a second-line therapy in many European countries including France for adults with persistent (i.e., disease duration of more than 3 months) or chronic (disease duration of more than 12 months) ITP. Rituximab leads to an overall response rate of only 40 % at 1 year but 29.5% of lasting (5 years and more) response The investigators have shown that the absence of response to rituximab in ITP could be explained by the settlement and expansion of long-lived autoreactive plasma cells in the spleen made possible by the high amount of BAFF. Belimumab is a fully humanized anti-BAFF/Blys monoclonal Ab licensed for SLE. Based on the preliminary results of a phase 2 open prospective pilot study performed in our center combining rituximab with i.v belimumab seems highly promising We hypothesized that combining subcutaneous belimumab weekly over a 24 weeks period (Arm A) with rituximab is superior to rituximab and subcutaneous placebo weekly over 24 weeks period (Arm B) to achieve an overall response at W52.
The study design will be a prospective randomized, double-blind, multicenter (international), superiority phase III clinical study
Age ≥ 18 years
Primary ITP defined according to the standard definition criteria (Rodeghiero, Blood 2008)
Previous response to corticosteroids and/or IgIV defined by a rise of platelet levels > 30 x 109/L with at least a twofold increase from baseline levels followed by a relapse.
Platelet count ≤ 30 x 109/L within the previous month or <50 x 109/L if presence of haemorrhagic events or other reason left up to investigator discretion.
Splenectomy
Previous treatment with rituximab or any B-cell targeted therapy
Common variable immunodeficiency
Previous treatment with cyclophosphamide or ciclosporin
Parallel
Combination of Rituximab with subcutaneous belimumab
DrugBelimumab 200 mg subcutaneous weekly (i.e., every 7 days ±1 day) starting from day 0 through week 24 with 1 g intravenous of Rituximab 7 days and 21 days after the randomization.
Combination of Rituximab with subcutaneous placebo
DrugPlacebo subcutaneous weekly (i.e., every 7 days ±1 day starting from day 0) starting from day 0 through week 24 with 1 g intravenous of Rituximab 7 days and 21 days after the randomization.
The overall response rate (CR + R) in both arms at W52
To assess the superiority at W52 of a combination subcutaneous belimumab weekly over a 24 weeks period (Arm A) or subcutaneous placebo weekly during 24 weeks period (Arm B) with rituximab (or biosimilar) (at a fixed dose of 1,000 mg on Day 7 and Days 21).
Number of patients developing a severe hypogammaglobulinemia in both arms
(gammaglobulin level \< 4 g/dl)
Duration of a severe hypogammaglobulinemia
Duration of a severe hypogammaglobulinemia in patients with such complication
Variation in gammaglobulin
Variation in gammaglobulin classes and subclass levels
Number of severe infections
Number of severe infections requiring hospitalization
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Assistance Publique - Hôpitaux de Paris
Lead sponsor
GlaxoSmithKline
Collaborator
