Exploring Durable Remission With Rituximab in Antineutrophil Cytoplasmic Antibody(ANCA)-Associated Vasculitis (ENDURRANCE-1)
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| ClinicalTrials.gov Identifier: NCT03942887 |
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Recruitment Status :
Recruiting
First Posted : May 8, 2019
Last Update Posted : May 20, 2022
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| Condition or disease | Intervention/treatment | Phase |
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| ANCA Associated Vasculitis | Drug: Rituximab Drug: endoxan Drug: Methylprednisolone Drug: Prednisolone | Phase 3 |
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
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 100 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | open-label, 1:1 randomized, prospective study between RTX with cyclophosphamide and RTX alone. |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Evaluating Clinical and Immunological Effects of Rituximab With Cyclophosphamide Compared to Rituximab Alone in AAV Patients |
| Actual Study Start Date : | May 3, 2019 |
| Estimated Primary Completion Date : | April 1, 2025 |
| Estimated Study Completion Date : | April 1, 2025 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: 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.
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Drug: 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.
Other Name: anti-cd20 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.
Other Name: solumedrol Drug: Prednisolone after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations
Other Name: corticosteroid |
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Active Comparator: 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.
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Drug: 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.
Other Name: anti-cd20 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.
Other Name: cyclophosphamide 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.
Other Name: solumedrol Drug: Prednisolone after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations
Other Name: corticosteroid |
- Number of tailored RTX infusions [ Time Frame: 2 years ]The primary outcome is the number of RTX infusions needed to maintain clinical remission over 2 years
- Time [ Time Frame: 2 years ]- time to a ANCA negative test
- ANCA reappearance [ Time Frame: 2 years ]- Percentage of patients that have ANCA return during follow-up
- B cell depletion [ Time Frame: 2 years ]- duration of B-cell depletion
- Remission and relaps rate [ Time Frame: 2 years ]- to compare disease controle between arms
- Number of adverse events [ Time Frame: 2 years ]- to assess the safety parameters of each treatment arm including adverse events according to WHO toxicity criteria, time to immune reconstitution and recording of infectious events
- Quality of Life [ Time Frame: 2 years ]assess quality of life by AAV-PRO
- BVAS [ Time Frame: 2 years ]Disease activity will be assessed by BVAS
- concomitant immunosuppressants [ Time Frame: 2 years ]Disease activity assessed by (the reduction of) concomitant immunosuppressants
- Kidney function [ Time Frame: 2 years ]Return of kidney function will be assessed.
- Biomarker for inflammation [ Time Frame: 2 years ]Disease activity assessed by ESR
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Subjects enrolled in the study must meet the following inclusion criteria:
- Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions26
- 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
- Positive test for anti-PR3 or anti-MPO (current or historic)
- Willing and able to give written Informed Consent and to comply with the requirements of the study protocol
Exclusion criteria:
Subjects will be excluded from participation if they meet any of the following exclusion criteria:
- Pregnant or breast-feeding
- Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
- Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
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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
- Have a history of a primary immunodeficiency
- Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study
- Have a neutrophil count of < 1.5x10E9/L
- Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin > 3 times the upper limit of normal before start of dosing
- Have any other clinically significant abnormal laboratory value in the opinion of the investigator
- Required dialysis or plasma exchange within 12 weeks prior to screening
- Received intravenous glucocorticoids, >3000mg methylprednisolone equivalent, within 4 weeks prior to screening
- Immunization with a live vaccine 1 month before screening
- 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.
- Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03942887
| Contact: YKO Teng, MD, PhD | +31715262148 | y.k.o.teng@Lumc.nl |
| Netherlands | |
| Leiden University Medical Center | Recruiting |
| Leiden, Zuid-Holland, Netherlands, 2333ZA | |
| Contact: YKO Teng, MD, PhD +31715268157 y.k.o.teng@lumc.nl | |
| Noordwest Ziekenhuisgroep | Not yet recruiting |
| Alkmaar, Netherlands | |
| Meander Medical Center | Recruiting |
| Amersfoort, Netherlands | |
| HagaZiekenhuis | Not yet recruiting |
| Den Haag, Netherlands | |
| Principal Investigator: | YKO Teng, MD, PhD | LUMC Leiden |
| Responsible Party: | Y.K.Onno Teng, Nephrologist, head of outpatient clinic nephrology department, drs. Y.K.O. Teng, Leiden University Medical Center |
| ClinicalTrials.gov Identifier: | NCT03942887 |
| Other Study ID Numbers: |
NL67515.058.18 |
| First Posted: | May 8, 2019 Key Record Dates |
| Last Update Posted: | May 20, 2022 |
| Last Verified: | May 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
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ANCA Crescentic glomerulonephritis systemic autoimmune disease Renal failure |
Renal insufficiency small vessel vasculitis GPA MPA |
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Vasculitis Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Vascular Diseases Cardiovascular Diseases Systemic Vasculitis Autoimmune Diseases Immune System Diseases Methylprednisolone Methylprednisolone Acetate Methylprednisolone Hemisuccinate Prednisolone Prednisolone acetate Cyclophosphamide Rituximab Prednisolone hemisuccinate |
Prednisolone phosphate Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antineoplastic Agents, Immunological Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents |