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Efficacy and Safety Assessment of a Treatment Combining Rituximab and Belimumab in Adults With Persistent Immune Thrombocytopenia (RITUX PLUS)

Primary Purpose

Immune Thrombocytopenia

Status

Completed

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

Rituximab (Mabthera ®) Belimumab (Benlysta ®)

About this trial

This is an interventional treatment trial for Immune Thrombocytopenia focused on measuring ITP

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age ≥ 18 years, <75 years
Primary ITP diagnostic defined according to the standard definition criteria (Rodeghiero et al Blood 2008)
Previous transient response to first-line treatments of corticosteroids and/or IgIV characterized by a rise of platelet levels > 30 G/L with at least a twofold increase from baseline levels followed by a relapse.
Platelet count ≤ 30,000 /µL at inclusion or <50 G/L if presence of hemorrhagic events or other reason left up to investigator discretion.
A persistent ITP active and existing for more than 3 months but less than 5 years from diagnosis.
Normal Bone marrow smear for patients above 60 years of age
Negative pregnancy test results for women of procreation age
Gammaglobulin level > 7 g/L
Informed consent

Exclusion Criteria:

Splenectomy
Previous treatment by Rituximab or any B-cell targeted therapy
Previous treatment by cyclophosphamide
No medical treatments of a therapeutic protocol nature within the last 30 days
Previous anaphylactic shock
Previous septic shock or severe sepsis
Chronic and ongoing severe infection requiring treatment or hospitalization in the 60 days preceding inclusion.
Severe acute infection within the last 4 weeks
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
History of primary immunodeficiency, IgG level < 400 mg/dl and/or IgA level < 10 mg/dl
Have 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.
Secondary ITP
History of recurrent infections
Neutrophils count < 1,000/mm3 at inclusion
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
New York Heart Classification III or IV heart disease
Treatment by antiaggregant/antiplatelet or anti-vitamin K drug
Previous history of malignancy in the last 5 years other than cutaneous carcinoma
Previous history of severe psychiatric disorder or previous suicide attempts in the last 6 months or suicidal thoughts in the last 2 months leading up to inclusion
Unable to comply with study and follow-up procedures due to psychiatric disorders or any other reason
Alcohol or drug abuse or dependence, either current or within 1year
Pregnancy or Breast-Feeding
Live, attenuated vaccinations must be administered at least 30 days before inclusion in study
History of significant medical illness or clinically significant laboratory abnormality (or planned surgical procedure) which in the opinion of the investigator would interfere with the study procedures and / or assessments or compromise subject safety

Sites / Locations

Henri Mondor Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

arm 1

Arm Description

Two intravenous perfusions of 1 g of Rituximab (Mabthera ®) at W0 and W2 coupled with 100 mg intravenous methylprednisone to avoid potential allergic reactions. Five belimumab (Benlysta ®) injections will be administered (W0 + 2days, W2 + 2 days, W4, W8, W12) at 10mg/kg doses. The first two injections are administered 2 days after Rituximab perfusions. The adopted experimental scheme was once used to show use of belimumab in systemic lupus erythematosus in accordance with AMM regulation

Outcomes

Primary Outcome Measures

The total number of patient responses to treatment, in other words sum of complete responses + responders

A responder (R) to treatment is defined by a patient with a maintained platelet count at >30x109/L (Rodeghiero et al Blood 2008) and a minimum twofold increase from initial platelet levels in the absence of bleeding and/or use of ITP directed therapies between Week 6 and Week 52 of patient follow-up. A complete response (CR) is defined by a platelet count > 100 x 109/L maintained in the absence of any other ITP directed therapies between Week 6 and Week 52. A Non-Responder (NR) is a patient with one or all of the following : Platelet count less than < 30 x 109/L by the end of study Require a rescue therapy (a new course of corticosteroids and/or intravenous immunoglobulin) more than 6 weeks after inclusion. Underwent any other treatment for ITP over the study period

Secondary Outcome Measures

Number of patients developing a severe hypogammaglobulinemia (gammaglobulin level < 4 g/dl)

Evolution of gammaglobulin levels

Duration of severe hypogammaglobulinemia in patients with such complication

Variation in gammaglobulin subclass levels throughout the study

Number of severe infections requiring hospitalization

Platelet Levels

Total number of responders (responders + complete responses)

Full Information

NCT ID

NCT03154385

First Posted

April 13, 2017

Last Updated

February 17, 2020

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT03154385

Brief Title

Efficacy and Safety Assessment of a Treatment Combining Rituximab and Belimumab in Adults With Persistent Immune Thrombocytopenia

Acronym

RITUX PLUS

Official Title

RITUX-PLUS. A Prospective Open Trial to Assess the Efficacy and Safety of a Treatment Combining Rituximab and Belimumab in Adults With Persistent Immune Thrombocytopenia.

Study Type

Interventional

2. Study Status

Record Verification Date

February 2020

Overall Recruitment Status

Completed

Study Start Date

March 13, 2017 (Actual)

Primary Completion Date

November 13, 2019 (Actual)

Study Completion Date

November 13, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Previous studies have shown that increase level of BAFF could promote the settlement of long-lived plasma cells in the spleen of ITP patients treated with anti-CD20. This single-center prospective pilot study, currently in phase IIa, will evaluate the efficacy of a rituximab and belimumab sequential combination treatment. Investigators plan to include 15 patients with persistent ITP over a 24-month inclusion period. Each patient will be followed for 1 year

Detailed Description

This single-center prospective pilot study, currently in phase IIa, evaluates the efficacy of a rituximab and belimumab sequential combination treatment. Based on the Fleming method, this study scheme includes a single step method. Eligible patients, having given consent and having been verified for inclusion criteria, will receive two intravenous perfusions of 1 g of Rituximab (Mabthera ®) at W0 and W2 coupled with 100 mg intravenous methylprednisone to avoid potential allergic reactions. Five belimumab (Benlysta ®) injections will be administered (W0 + 2days, W2 + 2 days, W4, W8, W12) at 10mg/kg doses. The first two injections are administered 2 days after Rituximab perfusions. The adopted experimental scheme was once used to show use of belimumab in systemic lupus erythematosus in accordance with AMM regulation. This phase II prospective single-center open-trial will be conducted at the National Referral Center for Adult Immune Cytopenia located in the Henri Mondor University Hospital. Investigators plan to include 15 patients with persistent ITP over an 24-month inclusion period. Each patient will be followed for 1 year

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Immune Thrombocytopenia

Keywords

ITP

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

15 (Actual)

8. Arms, Groups, and Interventions

Arm Title

arm 1

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Rituximab (Mabthera ®) Belimumab (Benlysta ®)

Intervention Description

Rituximab (Mabthera ®): 1g IV at W0 and W2 Belimumab (Benlysta ®) : 10mg/kg IV, W0 + 2days, W2 + 2 days, W4, W8, W12

Primary Outcome Measure Information:

Title

The total number of patient responses to treatment, in other words sum of complete responses + responders

Description

Time Frame

Week 52

Secondary Outcome Measure Information:

Title

Number of patients developing a severe hypogammaglobulinemia (gammaglobulin level < 4 g/dl)

Time Frame

at weeks 12, 24, 36, and 52

Title

Evolution of gammaglobulin levels

Time Frame

at weeks 4, 8, 12, 24, 36, and 52

Title

Duration of severe hypogammaglobulinemia in patients with such complication

Time Frame

Week 24

Title

Variation in gammaglobulin subclass levels throughout the study

Time Frame

at weeks 0,12, 24, 36, 52

Title

Number of severe infections requiring hospitalization

Time Frame

at weeks 24, 36 and 52

Title

Platelet Levels

Time Frame

at weeks 4, 8, 12, 24, 36, and 52

Title

Total number of responders (responders + complete responses)

Time Frame

at weeks 12,25, and 36

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age ≥ 18 years, <75 years Primary ITP diagnostic defined according to the standard definition criteria (Rodeghiero et al Blood 2008) Previous transient response to first-line treatments of corticosteroids and/or IgIV characterized by a rise of platelet levels > 30 G/L with at least a twofold increase from baseline levels followed by a relapse. Platelet count ≤ 30,000 /µL at inclusion or <50 G/L if presence of hemorrhagic events or other reason left up to investigator discretion. A persistent ITP active and existing for more than 3 months but less than 5 years from diagnosis. Normal Bone marrow smear for patients above 60 years of age Negative pregnancy test results for women of procreation age Gammaglobulin level > 7 g/L Informed consent Exclusion Criteria: Splenectomy Previous treatment by Rituximab or any B-cell targeted therapy Previous treatment by cyclophosphamide No medical treatments of a therapeutic protocol nature within the last 30 days Previous anaphylactic shock Previous septic shock or severe sepsis Chronic and ongoing severe infection requiring treatment or hospitalization in the 60 days preceding inclusion. Severe acute infection within the last 4 weeks 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 History of primary immunodeficiency, IgG level < 400 mg/dl and/or IgA level < 10 mg/dl Have 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. Secondary ITP History of recurrent infections Neutrophils count < 1,000/mm3 at inclusion 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 New York Heart Classification III or IV heart disease Treatment by antiaggregant/antiplatelet or anti-vitamin K drug Previous history of malignancy in the last 5 years other than cutaneous carcinoma Previous history of severe psychiatric disorder or previous suicide attempts in the last 6 months or suicidal thoughts in the last 2 months leading up to inclusion Unable to comply with study and follow-up procedures due to psychiatric disorders or any other reason Alcohol or drug abuse or dependence, either current or within 1year Pregnancy or Breast-Feeding Live, attenuated vaccinations must be administered at least 30 days before inclusion in study History of significant medical illness or clinically significant laboratory abnormality (or planned surgical procedure) which in the opinion of the investigator would interfere with the study procedures and / or assessments or compromise subject safety

Facility Information:

Facility Name

Henri Mondor Hospital

City

Creteil

ZIP/Postal Code

94010

Country

France

12. IPD Sharing Statement

Citations:

PubMed Identifier

32817288

Citation

Mahevas M, Azzaoui I, Crickx E, Canoui-Poitrine F, Gobert D, Languille L, Limal N, Guillaud C, Croisille L, Jeljeli M, Batteux F, Baloul S, Fain O, Pirenne F, Weill JC, Reynaud CA, Godeau B, Michel M. Efficacy, safety and immunological profile of combining rituximab with belimumab for adults with persistent or chronic immune thrombocytopenia: results from a prospective phase 2b trial. Haematologica. 2021 Sep 1;106(9):2449-2457. doi: 10.3324/haematol.2020.259481.

Results Reference

derived

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Efficacy and Safety Assessment of a Treatment Combining Rituximab and Belimumab in Adults With Persistent Immune Thrombocytopenia

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