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

NCT03942887 | Unknown Phase 3 DMC

• 1 other identifier: NL67515.058.18
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 4

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.

Conditions

ANCA Associated Vasculitis

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Number of tailored RTX infusions

  The primary outcome is the number of RTX infusions needed to maintain clinical remission over 2 years

  2 years

Secondary Outcomes (10)

• Time

  2 years

• ANCA reappearance

  2 years

• B cell depletion

  2 years

• Remission and relaps rate

  2 years

• Number of adverse events

  2 years

Study Arms (2)

Rituximab

ACTIVE COMPARATOR

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; Drug: Methylprednisolone; Drug: Prednisolone

Rituximab plus low-dose cyclophosphamide

ACTIVE COMPARATOR

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; Drug: endoxan; Drug: Methylprednisolone; Drug: Prednisolone

Interventions

Rituximab 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.

Also known as: anti-cd20

Rituximab; Rituximab plus low-dose cyclophosphamide

endoxan 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.

Also known as: cyclophosphamide

Rituximab plus low-dose cyclophosphamide

Methylprednisolone 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.

Also known as: solumedrol

Rituximab; Rituximab plus low-dose cyclophosphamide

Prednisolone DRUG

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

Also known as: corticosteroid

Rituximab; Rituximab plus low-dose cyclophosphamide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• 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.

Sponsors & Collaborators

• Leiden University Medical Center: lead

Study Sites (4)

Leiden University Medical Center

Leiden, South Holland, 2333ZA, Netherlands

RECRUITING

Noordwest Ziekenhuisgroep

Alkmaar, Netherlands

NOT YET RECRUITING

Meander Medical Center

Amersfoort, Netherlands

RECRUITING

HagaZiekenhuis

The Hague, Netherlands

NOT YET RECRUITING

Related Publications (1)

• 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.

  PMID: 36130755 DERIVED

MeSH Terms

Conditions

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Renal Insufficiency

Interventions

Rituximab; Cyclophosphamide; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone; Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Systemic Vasculitis; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• YKO Teng, MD, PhD

  LUMC Leiden

  PRINCIPAL INVESTIGATOR

Central Study Contacts

YKO Teng, MD, PhD

CONTACT

+31715262148; y.k.o.teng@Lumc.nl

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Nephrologist, head of outpatient clinic nephrology department, drs. Y.K.O. Teng

Model Details: open-label, 1:1 randomized, prospective study between RTX with cyclophosphamide and RTX alone.

Study Record Dates

• First Submitted: April 8, 2019
• First Posted: May 8, 2019
• Study Start: May 3, 2019
• Primary Completion: April 1, 2025
• Study Completion: April 1, 2025
• Last Updated: December 14, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

NL (4)