Efficacy and Safety of Subcutaneous Belimumab or Placebo in Addition of Rituximab in Persistent or Chronic Immune Thrombocytopenia

NCT05338190 | Recruiting Phase 3 DMC

• 2 other identifiers: APHP2010982021-000006-16
• Study Type: interventional
• Target: 132
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Primary Immune Thrombocytopenia (ITP)

Outcome Measures

Primary Outcomes (1)

• 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).

  Week 52

Secondary Outcomes (8)

• Number of patients developing a severe hypogammaglobulinemia in both arms

  at Week 12, Week 24, Week 36, Week 52, Week 88, Week 104

• Duration of a severe hypogammaglobulinemia

  up to Week 104

• Variation in gammaglobulin

  Frame throughout the study (Week 0, Week 12, Week 24, Week 36, Week 52, Week 88, Week 104)

• Number of severe infections

  up to Week 104

• Platelet levels

  at Week 6, Week 12, Week 24, Week 36, Week 52, Week 88, Week 104

Study Arms (2)

ARM A

EXPERIMENTAL

Belimumab 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.

Drug: Combination of Rituximab with subcutaneous belimumab

ARM B

PLACEBO COMPARATOR

Placebo 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.

Drug: Combination of Rituximab with subcutaneous placebo

Interventions

Combination of Rituximab with subcutaneous belimumab DRUG

Belimumab 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.

ARM A

Combination of Rituximab with subcutaneous placebo DRUG

Placebo 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.

ARM B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• ITP duration of more than 2 months but less than 5 years from diagnosis.
• Normal bone marrow smear for patients above 60 years of age
• Negative pregnancy test results and effective contraception for women of childbearing age Female subjects of childbearing potential must not become pregnant and so must be sexually inactive by abstinence or use contraceptive methods with a failure rate of \< 1%.
• Therefore, these women must have a negative serum pregnancy test at screening, and confirmed monthly while in study (with serum or Urine test), out to at least 12 months (taking account of the longest half-life which is that of 29.7 days and according to smPC) post last dose and agree to 1 of the following:
• Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 16 weeks after the last dose of study agent (Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception) OR
• Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month prior to the start of the study agent, during the study, and 16 weeks after the last dose of study agent
• Oral contraceptive, either combined or progestogen alone
• Injectable progestogen
• Implants of levonorgestrel or etonogestrel
• Estrogenic vaginal ring
• Percutaneous contraceptive patches

You may not qualify if:

• Splenectomy
• Previous treatment with rituximab or any B-cell targeted therapy
• Common variable immunodeficiency
• Previous treatment with cyclophosphamide or ciclosporin
• Previous anaphylactic shock to previous biologic therapy
• Use of parenteral antibiotics within 60 days, current use of suppressive therapy for chronic infection such as tuberculosis, pneumocystis, cytomegalovirus, HSZ, herpes zoster, and atypical mycobacteria
• Evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, pose a significant suicide risk.
• Psychiatric Illness impairing judgement.
• Positive HIV test and/or hepatitis virus C infection and/or positive hepatitis B virus surface antigen or core antibody (HbsAg or HBcAb)
• Impaired renal function as indicated by a serum creatinine level \> 2 mg/dl
• Liver function: AST (SGOT) and ALT (SGPT) ≥5xULN Total bilirubin ≥3 x ULN
• New York Heart Classification III or IV heart disease
• Previous history of malignancy in the last 5 years other than cutaneous carcinoma
• Previous history of Progressive multifocal leukoencephalopathy
• Previous history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

Henri Mondor Hospital

Créteil, 9400, France

RECRUITING

MeSH Terms

Conditions

Purpura, Thrombocytopenic, Idiopathic

Condition Hierarchy (Ancestors)

Purpura, Thrombocytopenic; Purpura; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Cytopenia; Hemorrhagic Disorders; Autoimmune Diseases; Immune System Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Manifestations; Signs and Symptoms

Central Study Contacts

Matthieu MAHEVAS, Professor of medicine

CONTACT

0 1 49 81 20 76; matthieu.mahevas@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind controlled trial
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 21, 2022
• First Posted: April 21, 2022
• Study Start: November 14, 2022
• Primary Completion (Estimated): November 14, 2026
• Study Completion (Estimated): November 14, 2027
• Last Updated: September 11, 2023

Record last verified: 2023-09

Locations

FR (1)