Exploring Durable Remission With Rituximab in Antineutrophil Cytoplasmic Antibody(ANCA)-Associated Vasculitis

NCT ID: NCT03942887

Last Updated: 2023-12-14

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-03
• Study Completion Date: 2025-04-01

Brief Summary

Most recent insights in the treatment for patients with ANCA-associated vasculitis (AAV) have demonstrated that 'tailored' maintenance treatment with rituximab (RTX) is effective to achieve durable remission of disease. As such, RTX re-treatment can be tailored on the basis of relevant clinical and immunological parameters in AAV patients. Now, the present study intends to evaluate whether combining rituximab with cyclophosphamide is superior to current standard of care with rituximab only to induce a favorable clinical and immunological state in AAV patients and can thereby reduce the number of tailored re-treatments with rituximab.

Detailed Description

Objectives: The primary objective is to prove that the combination of RTX and low-dose CYC reduces the number of RTX infusions needed to maintain clinical remission over 2 years. The secondary objectives are measurements for minimal residual auto-immunity (MRA) such as time to ANCA seronegativity, proportion of seronegativity, time to ANCA return, proportion of ANCA return, duration of B-cell depletion and the composition of the memory B-cell and plasma cell populations. Other secondary objectives are the potential association between MRA and disease flares, and the evaluation of (severe) adverse events, cost-effectiveness and quality of life Study design: open-label, multicenter, 1:1 randomized, prospective study Study population: Adult AAV patients with a clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have 'generalised disease' and a positive ANCA-test for anti-PR3 or anti-MPO.

Intervention: In addition to standard of care corticosteroid therapy, AAV patients will be randomized to receive either standard induction therapy with 2 infusions of RTX 1000 mg or induction therapy combining 2 infusions of RTX 1000 mg with 6 infusions of low dose intravenous cyclophosphamide 500mg. Thereafter, as part of standard of care patients will receive tailored RTX re-treatment as maintenance therapy.

Main study parameters: AAV patients will be evaluated for the cumulative number of events for tailored RTX retreatments needed to maintain clinical remission over 2 years. Also, AAV patients will be evaluated for MRA by prospectively and consecutively studying ANCA levels and B-cell depletion by standard flowcytometry at predefined timepoints. Additionally, the study will perform safety and toxicity monitoring according to WHO toxicity criteria and evaluate the clinical response, the number of moderate and severe flares during study follow-up, the cost-effectiveness, and the quality of life of patients.

Study duration: 2 years

Conditions

ANCA Associated Vasculitis

Keywords

ANCA; Crescentic glomerulonephritis; systemic autoimmune disease; Renal failure; Renal insufficiency; small vessel vasculitis; GPA; MPA

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rituximab

Patients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg.

Group Type: ACTIVE_COMPARATOR

Rituximab

Intervention Type: DRUG

Patients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg. At any time during the study, a rituximab biosimilar is allowed as a substitute for the bio-originator rituximab.

Methylprednisolone

Intervention Type: DRUG

Patients are given 1-3 pulses of 500mg methylprednisolone i.v. up to a maximum cumulative dose of 3000mg, taking into account any doses of intravenous methylprednisolone administered within 12 weeks prior to screening.

Prednisolone

Intervention Type: DRUG

after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations

Rituximab plus low-dose cyclophosphamide

5.1.2. Cyclophosphamide Patients will be intravenously treated with a total of 6 infusions of cyclophosphamide 500mg every 2 weeks. Before every infusion of cyclophosphamide patients will receive intravenous granisetron to prevent nausea.

Group Type: ACTIVE_COMPARATOR

Rituximab

Intervention Type: DRUG

Patients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg. At any time during the study, a rituximab biosimilar is allowed as a substitute for the bio-originator rituximab.

endoxan

Intervention Type: DRUG

Patients will be intravenously treated with a total of 6 infusions of cyclophosphamide 500mg every 2 weeks. Before every infusion of cyclophosphamide patients will receive intravenous granisetron to prevent nausea.

Methylprednisolone

Intervention Type: DRUG

Patients are given 1-3 pulses of 500mg methylprednisolone i.v. up to a maximum cumulative dose of 3000mg, taking into account any doses of intravenous methylprednisolone administered within 12 weeks prior to screening.

Prednisolone

Intervention Type: DRUG

after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations

Interventions

Rituximab

Patients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg. At any time during the study, a rituximab biosimilar is allowed as a substitute for the bio-originator rituximab.

Intervention Type: DRUG

endoxan

Patients will be intravenously treated with a total of 6 infusions of cyclophosphamide 500mg every 2 weeks. Before every infusion of cyclophosphamide patients will receive intravenous granisetron to prevent nausea.

Intervention Type: DRUG

Methylprednisolone

Patients are given 1-3 pulses of 500mg methylprednisolone i.v. up to a maximum cumulative dose of 3000mg, taking into account any doses of intravenous methylprednisolone administered within 12 weeks prior to screening.

Intervention Type: DRUG

Prednisolone

after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations

Intervention Type: DRUG

Other Intervention Names

anti-cd20; cyclophosphamide; solumedrol; corticosteroid

Eligibility Criteria

Inclusion Criteria

1. Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions26

2. Aged at least 18 years, with newly-diagnosed or relapsed AAV with 'generalised disease', defined as involvement of at least one major organ (e.g. kidney, lung, heart, peripheral or central nervous system), requiring induction treatment with cyclophosphamide or rituximab

3. Positive test for anti-PR3 or anti-MPO (current or historic)

4. Willing and able to give written Informed Consent and to comply with the requirements of the study protocol

Exclusion Criteria

1. Pregnant or breast-feeding

2. Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG

3. Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)

4. Active infection not compatible with start of remission-induction therapy in the opinion of the treating physician and/or investigator, e.g.:

• Serological evidence of viral hepatitis defined as: patients positive for HbsAg test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication
• Have a historically positive HIV test or test positive at screening for HIV

5. Have a history of a primary immunodeficiency

6. Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study

7. Have a neutrophil count of < 1.5x10E9/L

8. Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin > 3 times the upper limit of normal before start of dosing

9. Have any other clinically significant abnormal laboratory value in the opinion of the investigator

10. Required dialysis or plasma exchange within 12 weeks prior to screening

11. Received intravenous glucocorticoids, >3000mg methylprednisolone equivalent, within 4 weeks prior to screening

12. Immunization with a live vaccine 1 month before screening

13. History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation.

14. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Y.K.Onno Teng

Nephrologist, head of outpatient clinic nephrology department, drs. Y.K.O. Teng

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

YKO Teng, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

LUMC Leiden

Locations

Leiden University Medical Center

Leiden, South Holland, Netherlands

Site Status: RECRUITING

Noordwest Ziekenhuisgroep

Alkmaar, , Netherlands

Site Status: NOT_YET_RECRUITING

Meander Medical Center

Amersfoort, , Netherlands

Site Status: RECRUITING

HagaZiekenhuis

The Hague, , Netherlands

Site Status: NOT_YET_RECRUITING

Countries

United Kingdom; Netherlands

Central Contacts

YKO Teng, MD, PhD

Role: CONTACT

Phone: +31715262148

Email: y.k.o.teng@Lumc.nl

Facility Contacts

YKO Teng, MD, PhD

Role: primary

References

Dirikgil E, van Leeuwen JR, Bredewold OW, Ray A, Jonker JT, Soonawala D, Remmelts HHF, van Dam B, Bos WJ, van Kooten C, Rotmans J, Rabelink T, Teng YKO. ExploriNg DUrable Remission with Rituximab in ANCA-associatEd vasculitis (ENDURRANCE trial): protocol for a randomised controlled trial. BMJ Open. 2022 Sep 21;12(9):e061339. doi: 10.1136/bmjopen-2022-061339.

Reference Type: DERIVED

PMID: 36130755 (View on PubMed)

Other Identifiers

NL67515.058.18

Identifier Type: -

Identifier Source: org_study_id