RemiRit - Personalized immunosuppressive therapy with rituximab in the treatment of ANCA associated vasculitis - a randomized, multicenter clinical trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

27 Nov 2022 → ongoing

Decision date (initial)

2024-11-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Agencja Badań Medycznych

External identifiers

EU CT number

2024-517881-40-00

EudraCT number

2021-006831-25

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Diagnosis, Safety, Efficacy

Part I - induction treatment: Comparison of the efficacy of combination treatment with rituximab (RTX) and cyclophosphamide (CYC) versus standard treatment with cyclophosphamide (CYC) in induction of complete remission of severe AAV, defined as BVAS/WG=0.
Part II - maintenance treatment: To compare the efficacy of subcutaneous and intravenous rituximab (RTX) treatment in sustaining complete (BVAS/WG=0) or partial (BVAS/WG=1 or2) remission of AAV.
Additional research objective: To evaluate genetic predisposition to disease development, disease course, and response to treatment.

Conditions and MedDRA coding

Antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Written informed consent of the patient to participate in the clinical trial.
2. Age ≥ 18 years.
3. Diagnosis of AAV, including granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) as defined by the Chapel Hill Consensus Conference.
4. New diagnosis or exacerbation of AAV.
5. High AAV activity defined as ≥ 3 points on the BVAS/WG scale.
6. Positive PR3-ANCA or MPO-ANCA at screening or within 30 days prior to screening.
7. Discontinuation of current immunosuppressive and immunomodulatory agents, including mycophenolate mofetil, azathioprine, methotrexate and leflunomide, no later than the day of screening.
8. Use of highly effective contraception by women of childbearing potential during the study and 12 months after the last administration of the investigational medicinal product.
9. Use of high barrier contraception by men with female partners of childbearing potential throughout the study and 6 months after the last administration of an investigational medicinal product.
10. Consent to prophylactically intake of Entecavir in case of a positive total anti-Hbc result with HBsAg.

Exclusion criteria 30

1. Diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) as defined by the Chapel Hill Consensus Conference.
2. Severe heart failure (New York Heart Association Class IV) or severe uncontrolled heart disease not due to AAV.
3. Acute or chronic liver disease, not due to AAV, which in the opinion of the Investigator is a contraindication to participation in the study.
4. History or presence of other relevant diseases that, in the opinion of the Investigator may adversely affect the patient's participation in the study.
5. Congenital or acquired immunodeficiency.
6. Current history of urinary tract obstruction.
7. History of hemorrhagic cystitis, bone marrow hypoplasia or malignancy during treatment with cyclophosphamide.
8. Bone marrow aplasia.
9. Screening findings: a. Leukopenia defined as a white blood cell (WBC) count below 4000/mm3, b. Neutropenia defined as a neutrophil count less than 1500/mm3, c. Thrombocytopenia defined as a platelet count (PLT) less than 100000/mm3, d. Hemoglobin (Hgb) less than 8.0 g/dl, e. AST or ALT elevations greater than 2.5 x GGN, not due to AAV, f. Severe immunoglobulin deficiency defined as IgG less than 400 mg/dL or IgA less than 10 mg/dL, g. Positive HBsAg, h. Positive anti-HCV result, i. Positive QuantiFERON-TB Gold test result, j. Positive anti-HIV 1 or anti-HIV 2
10. Positive pregnancy test performed among women of childbearing age at screening or Visit 1.
11. Medications being taken: a. Rituximab and other drugs that cause B-lymphocyte depletion within 6 months prior to screening, b. Cyclophosphamide within 6 months prior to screening, except when oral cyclophosphamide is included up to 7 days prior to screening and discontinued no later than the day of screening, c. Infliximab within 3 months prior to screening, d. Adalimumab within 2 months prior to screening, e. Etanercept within 1 month prior to screening.
12. Acute or chronic respiratory failure, not due to AAV.
13. Documented history of antichimeric antibody formation after administration of monoclonal antibodies.
14. Diagnosis of AAV limited to the kidney, without involvement of other organs.
15. Diagnosis of AAV with simultaneous presence of both MPO-ANCA and PR3-ANCA antibodies in serum.
16. Limited form of disease that does not require treatment with cyclophosphamide.
17. Respiratory failure due to diffuse alveolar hemorrhage requiring mechanical ventilation.
18. Diagnosis of disease associated with anti-glomerular basement membrane (anti-GBM) as defined by the Chapel Hill Consensus Conference.
19. Active or history of cancer within the past 5 years, except for basal-cell carcinoma of the skin and carcinoma in situ of cervix in patients who have received radical treatment.
20. Infections: a. Active and chronic viral, bacterial, fungal or parasitic infection b. Active or latent tuberculosis c. Active or chronic hepatitis B d. Active or chronic hepatitis C e. Diagnosed HIV infection.
21. History of severe allergic reactions to human or chimeric monoclonal antibodies or mouse proteins.
22. History of hypersensitivity to the active substance or any excipient of the investigational medicinal products (cyclophosphamide or rituximab).
23. History of intolerance to any of the investigational medicinal products (cyclophosphamide or rituximab).
24. History of allergy to drugs or other substances which, in the opinion of the Investigator is a contraindication to participation in the study.
25. Abuse of drugs, alcohol or other intoxicating substances.
26. Vaccination with live vaccines within 4 weeks prior to screening.
27. Pregnancy or planning a pregnancy during the study and 12 months after the study.
28. Breastfeeding or planning to breastfeed during the study and 12 months after completion of the study.
29. Participation in another clinical trial.
30. Lack of patient compliance.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part I induction treatment: The occurrence of complete remission (defined as BVAS/WG=0 disease activity) at 26 weeks after enrollment to Part I. Part II - Maintenance treatment: The occurrence of a positive treatment effect defined as complete remission (BVAS/WG=0 disease activity) or partial remission (BVAS/WG=1 or BVAS/WG=2) at 104 weeks after randomization to Part II.

Secondary endpoints 12

1. Treatment response defined as a >50% reduction in BVAS/WG vasculitis activity from baseline at 26 weeks after enrollment in Part I.
2. The occurrence of serious adverse events at 26 weeks after enrollment in Part I.
3. The occurence of non-serious adverse events at 26 weeks after enrollment in Part I.
4. The occurence of organ damage (based on VDI) at 26 weeks after enrollment in Part I.
5. Change at 13 and 26 weeks after enrollment in Part I from baseline: a. ANCA autoantibody titre, b. CD19+ lymphocyte count, c. Concentration of C5a component of complement, d. Creatinine concentration, e. eGFR.
6. The occurrence of a major relapse (defined as an increase in BVAS/WG score to ≥3 points, requiring reinitiation of remission-inducing treatment) at 26, 52, 78, and 104 weeks after randomization to Part II.
7. The occurrence of a minor relapse (defined as an increase in BVAS/WG score to 1-2 points, requiring only an increase in maintenance glucocorticosteroid dose) at 26, 52, 78, and 104 weeks after randomization to Part II.
8. The occurrence of serious adverse events at 26, 52, 78, and 104 weeks after randomization to Part II.
9. The occurrence of non-serious adverse events at 26, 52, 78, and 104 weeks from randomization to Part II.
10. The occurrence of organ damage (based on VDI) at 26, 52, 78, and 104 weeks after randomization to Part II.
11. Change at 26, 52, 78, and 104 weeks after randomization to Part II from baseline: a. ANCA autoantibody titers, b. CD 19+ lymphocyte count, c. Concentration of C5a component of complement, d. Creatinine concentration, e. eGFR.
12. Change at 26, 52, 78, and 104 weeks after randomization to Part II from baseline in quality of life as measured by the SF-36 form.

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Sponsor organisation

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Address

Ulica Szaserow 128

City

Warsaw

Postcode

04-141

Country

Poland

Scientific contact point

Organisation

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Contact name

Co-ordinating Investigator

Public contact point

Organisation

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Contact name

Sekcja Projektów Operacyjnych i Strategicznych

Locations

1 EU/EEA country · 6 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 8 files

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

Application history

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