E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ANCA associated vasculitis |
ANCA geassocieerde vasculitis |
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E.1.1.1 | Medical condition in easily understood language |
Small vessel vasculitis |
kleine vaten vasculitis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In this randomized study the primary objective is to prove the superiority of combination treatment RTX with cyclophosphamide to achieve a state of MRA in AAV patients as compared to RTX alone. The primary objective is to assess the time to an ANCA negative test.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are: - time to ANCA return - duration of B-cell depletion - composition of the memory B-cell and plasma cell compartment before and after treatment - to investigate whether MRA is associated with disease flares - to investigate whether MRA is associated with (a shorter) time to a disease flares - to investigate whether the presence or absence of MRA after RTX can guide a personalized treatment - 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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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
4.1. 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 |
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E.4 | Principal exclusion criteria |
4.2. Exclusion criteria Subjects will be excluded from participation if they meet any of the following 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) 5) Active infection at time of screening, as follows: - Hospitalization for treatment of infection within previous 60 days of day 0 of the study - Use of parenteral (intravenous of intramuscular) antibiotics (including anti-bacterials, anti-virals, anti-fungals or anti-parasitic agents) within previous 60 days of day 0 of the study - 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 6) Have a history of a primary immunodeficiency 7) Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study 8) Have a neutrophil count of < 1.5x10E9/L 9) Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin > 3 times the upper limit of normal before start of dosing 10) Have a CD19 count of < 40x106 cells/L (equal to < 40 cells/uL; equal to < 40 cells/mm3) 11) Have any other clinically significant abnormal laboratory value in the opinion of the investigator 12) Required dialysis or plasma exchange within 12 weeks prior to screening 13) Received intravenous glucocorticoids, >3000mg methylprednisolone equivalent, within 4 weeks prior to screening 14) Immunization with a live vaccine 1 month before screening 15) 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. 16) Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary immunological parameter will be the time to seroconversion of ANCA to negative, i.e. below the detection range of a high-quality ANCA immunoassay. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
SCR BL 2 4 8 12 16 20 24 32 40 48 56 64 72 80 88 96 104 EoS |
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E.5.2 | Secondary end point(s) |
- 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 - 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. > 1x106 cells/L) - composition of the memory B-cell and plasma cell compartment before and after treatment using standard and high-sensitivity flowcytometry - to investigate whether MRA is associated with disease flares where degrees of MRA are defined as seroconversion of ANCA to negative with or without B-cell depletion - to investigate whether MRA is associated with (a shorter) time to a disease flares - to assess the safety parameters of each treatment arm including adverse events according to WHO toxicity criteria and recording of infectious events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
SCR BL 2 4 8 12 16 20 24 32 40 48 56 64 72 80 88 96 104 EoS
experimental high sensitivity flow cytometry: scr, bl, 4, 12, 24, 40, 56, 72, 88, 104, eos |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |