RITUX-PLUS 2 : A phase 3 randomized and double-blind controlled trial comparing the efficacy and safety of rituximab combined with subcutaneous belimumab versus rituximab + placebo in adult patients with persistent or chronic immune thrombocytopenia (ITP)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

10 Nov 2022 → ongoing

Decision date (initial)

2024-11-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Research grant: funded by GSK

External identifiers

EU CT number

2024-516168-27-00

EudraCT number

2021-000006-16

ClinicalTrials.gov

NCT05338190

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

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)

Secondary objectives 8

1. To analyze the overall response (complete response + response) of patients throughout the study until W104
2. To assess the incidence of secondary hypogammaglobulinemia (<4 g/dl) in both arms at W12, W24, W36, W52, W78, W104
3. To assess levels of gammaglobulin classes and subclasses over the course of the study period
4. To compare in both arms the number of severe infections (requiring hospitalization), over the study period
5. To assess haemorrhagic events occurring throughout the study
6. To compare the rate and type anti-platelets antibodies in both arms at baseline at W24, W52, W104
7. Assessment of patients' quality of life at inclusion, Week 24 and Week 52
8. Objective of Ancillary Study : a) To analyze the change of B-cell subpopulations in peripheral blood under treatment and during B-cell reconstitution at W0, W12, W24, W36, W52, W78, W104. b) To analyse BAFF and pro-inflammatory cytokines at W0, W12, W24, W36, W52, W78, W104. c) To analyse the change of T-CD4+ helper follicular subsets W0, W12, W24, W36, W52, W78, W104.

Conditions and MedDRA coding

Adult patients with persistent or chronic immune thrombocytopenia

Regulatory references

Plan to share IPD

Yes

IPD plan description

All of the individual participant data collected during the trial, subject to compliance to regulations, will be available. Document (Study protocol, statistical analysis plan, informed consent form, clinical study report, analytic code) will be also available. Data will be available immediately following publication ending 2 years after publication, with investigators whose proposed use of the data has been approved by the PI and / or the review commitee if relevant. Proposals should be directed to [email protected]. To gain access, data requestors will need to sign a data access agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age ≥ 18 years
2. Informed consent
3. Affiliated to, or beneficiary of, a social security regime or similar
4. Primary ITP defined according to the standard definition criteria (Rodeghiero, Blood 2008)
5. 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.
6. Platelet count ≤ 30 x 109/L within the previous month or <50 x 109/L G/L if presence of haemorrhagic events or other reason left up to investigator discretion.
7. ITP duration of more than 2 months but less than 10 years from diagnosis.
8. 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%.
9. Gammaglobulin level ≥ 7 g/L

Exclusion criteria 29

1. Splenectomy
2. Previous history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant.
3. Alcohol or drug abuse or dependence, either current or within 1year
4. Previous treatment with rituximab or any B-cell targeted therapy
5. Pregnant or breast-feeding woman
6. Live, attenuated vaccinations must be administered at least 30 days before inclusion in study
7. 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
8. Body mass index > 40
9. Vulnerable persons, under the protection of justice,
10. Persons deprived of their liberty by judicial or administrative decision
11. Persons admitted to a health or social establishment for purposes other than research
12. Psychiatric Illness impairing judgment
13. Persons under legal protection (guardianship, curatorship),
14. Persons unable to express their consent
15. Common variable immunodeficiency
16. Previous treatment with cyclophosphamide or ciclosporin
17. Inclusion in another clinical trial less than 3 months before inclusion
18. Previous anaphylactic shock
19. Chronic or ongoing severe infection requiring treatment or hospitalization in the 60 days preceding inclusion
20. 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
21. 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.
22. Neutrophils count < 1,000/mm3 at inclusion
23. Positive HIV test and/or hepatitis virus C infection and/or positive hepatitis B virus surface antigen or core antibody (HbsAg or HBcAb)
24. Impaired renal function as indicated by a serum creatinine level > 2 mg/dl
25. Liver function: AST (SGOT) and ALT (SGPT) ≥5xULN Total bilirubin ≥3 x ULN
26. New York Heart Classification III or IV heart disease
27. Previous history of malignancy in the last 5 years other than cutaneous carcinoma
28. Previous history of Progressive multifocal leukoencephalopathy
29. Previous history of Severe cutaneous adverse reactions (Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The overall response rate (CR + R) in both arms at W52

Secondary endpoints 9

1. Total number of responders (responders + complete responses) at W6, W12, W 24, W36, W52, W78, W104.
2. Duration of severe hypogammaglobulinemia in patients with such complication
3. Number of patients developing a severe hypogammaglobulinemia (gammaglobulin level < 4 g/dl) in both arms at W12, W24, W36, W52, W78, W104
4. Variation in gammaglobulin classes and subclass levels throughout the study (W0, W12, W24, W36, W52, W78, W104)
5. Number of severe infections requiring hospitalization during the study
6. Number of haemorrhagic events evaluated by the Khellaf Score at W6, W12, W24, W36, W52, W78, W104.
7. Platelet levels at W6, W12, W 24, W36, W52, W78, W104
8. Use of the SF-36 health questionnaire and FACIT-Fatigue scale (Functional assessment of chronic illness therapy) to assess patient’s quality of life at inclusion, W12, W24 and W52
9. Percentage of each B-cell subpopulation, T Follicular helper population and levels of cytokines (including BAFF) and anti-platelet antibodies at W12, W24, W36, W52, W78, W104.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Mathieu MAHEVAS

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Mathieu MAHEVAS

Locations

1 EU/EEA country · 38 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications