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Trial record 1 of 15 for:    "Anca-Associated Vasculitis" | "Prednisolone hemisuccinate"
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Exploring Durable Remission With Rituximab in Antineutrophil Cytoplasmic Antibody(ANCA)-Associated Vasculitis (ENDURRANCE-1)

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ClinicalTrials.gov Identifier: NCT03942887
Recruitment Status : Recruiting
First Posted : May 8, 2019
Last Update Posted : May 8, 2019
Sponsor:
Information provided by (Responsible Party):
YTeng, Leiden University Medical Center

Brief Summary:
Rationale: 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 immunological parameters that reflect minimal residual autoimmunity (MRA) 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 immunological state of MRA in AAV patients that can beneficially influence, i.e. reduce, the necessity of tailored re-treatment with rituximab

Condition or disease Intervention/treatment Phase
ANCA Associated Vasculitis Drug: Rituximab Drug: endoxan Drug: Methylprednisolone Drug: Prednisolone Phase 3

Detailed Description:

Objectives: The primary objective is to prove the superiority of combination treatment RTX with cyclophosphamide to achieve a state of MRA as defined as number of patients that reach ANCA seroconversion to negative within 24 weeks. The secondary objectives are alternative measurements for MRA such as time to ANCA return, duration of B-cell depletion and the composition of the memory B-cell and plasma cell populations.

Study design: Open label, two-center, randomized controlled trial 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-proteinase-3 (PR3) or anti-myeloperoxidase (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 RTX 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 MRA by prospectively and consecutively studying ANCA levels, B-cell depletion by standard flowcytometry and subsets of the B-cell and plasma cell compartment with high-sensitivity flowcytometry at predefined timepoints. Additionally, the study will perform safety and toxicity monitoring according to World Health Organization (WHO) toxicity criteria and evaluate the clinical response, the number of RTX re-treatments and the number of moderate and severe flares during study follow-up.

Study duration: 2 years


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 47 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 Favorable, Immunological Effects of Rituximab With Cyclophosphamide Compared to Rituximab Alone in AAV Patients
Estimated Study Start Date : May 10, 2019
Estimated Primary Completion Date : April 1, 2022
Estimated Study Completion Date : April 1, 2023


Arm Intervention/treatment
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.
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

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.
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




Primary Outcome Measures :
  1. Negative ANCA status [ Time Frame: 24 weeks ]
    The primary objective is to assess the number of patients that reach a ANCA negative test within 24 weeks of therapy.


Secondary Outcome Measures :
  1. Time [ Time Frame: 2 years ]
    - time to a ANCA negative test

  2. ANCA reappearance [ Time Frame: 2 years ]
    - Percentage of patients that have ANCA return during follow-up

  3. RTX maintenance [ Time Frame: 2 years ]
    - number of Rituximab infusions as maintenance therapy

  4. B cell depletion [ Time Frame: 2 years ]
    - duration of B-cell depletion

  5. The composition of the memory B-cell and plasma cell compartment before and after treatment [ Time Frame: 2 years ]
    The composition of the memory B-cell and plasma cell compartment before and after treatment will be assessed by using highly sensitive flow cytometry

  6. Time to disease flares [ Time Frame: 2 years ]
    - to investigate whether MRA is associated with (a shorter) time to a disease flares

  7. 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects enrolled in the study must meet the following 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

Information from the National Library of Medicine

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


Contacts
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Contact: YKO Teng, MD, PhD +31715262148 y.k.o.teng@Lumc.nl

Locations
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Netherlands
Leiden University Medical Center Recruiting
Leiden, Zuid-Holland, Netherlands, 2333ZA
Contact: YKO Teng, MD, PhD    +31715268157    y.k.o.teng@lumc.nl   
United Kingdom
Hammersmith Hospital Not yet recruiting
London, United Kingdom
Contact: Stephen McAdoo, MD, PhD         
Sponsors and Collaborators
Leiden University Medical Center
Investigators
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Principal Investigator: YKO Teng, MD, PhD LUMC Leiden
Principal Investigator: S. McAdoo, MD, PhD Hammersmith Hospital, Imperial College London

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Responsible Party: YTeng, Nephrologist, head of outpatient clinic nephrology department, drs. Y.K.O. Teng, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT03942887     History of Changes
Other Study ID Numbers: NL67515.058.18
First Posted: May 8, 2019    Key Record Dates
Last Update Posted: May 8, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by YTeng, Leiden University Medical Center:
ANCA
Crescentic glomerulonephritis
systemic autoimmune disease
Renal failure
Renal insufficiency
small vessel vasculitis
GPA
MPA
Additional relevant MeSH terms:
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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Prednisolone
Methylprednisolone Acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Vasculitis
Vascular Diseases
Cardiovascular Diseases
Systemic Vasculitis
Autoimmune Diseases
Immune System Diseases
Cyclophosphamide
Rituximab
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
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists