Evaluating, clinical and immunological effects of rituximab with cyclophosphamide compared to rituximab alone in AAV patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Academisch Ziekenhuis Leiden

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

3 May 2019 → ongoing

Decision date (initial)

2024-08-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-507868-39-00

EudraCT number

2018-003588-69

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

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

Secondary objectives 3

1. Measurements for minimal residual autoimmunity (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
2. The potential association between MRA and disease flares
3. The evaluation of (severe) adverse events, cost-effectiveness and quality of life

Conditions and MedDRA coding

ANCA Vasculitis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions
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 14

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Compare the number of RTX retreatment infusions needed to maintain clinical remission over 2 years, based on B-cell status and ANCA status, in both arms

Secondary endpoints 6

1. Assess the time to an ANCA negative test by using a high-quality ELISA measuring ANCAs. A negative test is defined as below the detection level
2. Assess the time to ANCA return defined as seroconversion to positive on at least 2 consecutive visits (the time of the first is then representative time of seroconversion) OR a doubling of the ANCA serum levels PR3 or MPO ELISA test compared to a previously achieved nadir
3. Duration of B-cell depletion defined as time taken to detect a repopulation of B-cells above the detection limit of standard flowcytometry (i.e. > 1x10^6 cells/L)
4. To assess the safety parameters of each treatment arm including adverse events according to WHO toxicity criteria and recording of infectious events
5. To assess quality of life by patient related outcome scores (AAV-PRO and SNOT22)
6. To assess clinical disease activity of each treatment arm as described in section 7.2.3 of the protocol

Investigational products

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

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Academisch Ziekenhuis Leiden

Sponsor organisation

Academisch Ziekenhuis Leiden

Address

Albinusdreef 2

City

Leiden

Postcode

2333 ZA

Country

Netherlands

Scientific contact point

Organisation

Academisch Ziekenhuis Leiden

Contact name

Y.K.O. Teng

Public contact point

Organisation

Academisch Ziekenhuis Leiden

Contact name

Y.K.O. Teng

Locations

1 EU/EEA country · 8 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 5 files

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

Application history

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