RITUXVAS

Background

1.1.The diseases

Wegener's granulomatosis (WG) and microscopic polyangiitis (MP) are syndromes of primary systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) (appendix 1)(15,16,19). WG and MP share many histological features, including a necrotising glomerulonephritis which often leads to rapidly progressive renal failure. Isolated pauci-immune necrotising, cresentic glomerulonephritis, has many features to suggest that it represents a renal-limited form of vasculitis (RLV), including the presence of circulating anti-MPO or anti-Pr3 antibodies. Common histological and serological features, and a similar response to treatment, have justified a common approach to the treatment of WG, MP and RLV. These diseases are sub grouped according to severity. ‘Generalised’ vasculitis refers to systemic disease with renal involvement (creatinine up to 500) and or other imminent vital organ failure. Patients with ‘generalised’ vasculitis and those with more severe renal vasculitis (i.e. creatinine greater than 500) will be included in this trial.

1.2.Their treatment

Untreated generalised WG and MP follow a progressive course with fatal outcome due to vital organ failure (17). With the empirical introduction of corticosteroids and cytotoxic agents, five year survival has increased from under 20% to over 60% (18). Over the last decade the treatment of AASV has been standardised following the results of randomised trials. Cyclophosphamide (either daily oral or intravenous (IV) pulse) and prednisolone are used for remission induction (3 to 6 months) with longer therapy of azathioprine or methotrexate and low dose steroids to prevent disease relapse. Early systemic vasculitis may be treated with methotrexate in place of cyclophosphamide. The addition of plasma exchange improves renal recovery rates in severe renal vasculitis. Adverse events with current therapy are frequent and are the major cause of mortality. The frequency of severe adverse events (10-45%) is influenced by age and the severity of renal involvement. There is a clear need for a new safer, effective therapy for AASV (1,2,3,6). In order to address the questions of drug toxicity and frequent disease relapses, newer therapies with better safety profiles have been investigated in AASV. One such agent is rituximab, a murine/human chimeric anti CD 20 monoclonal antibody. Its use results in B cell depletion for 6-18 months (7). B cells are key factors in autoimmune diseases with roles in autoantibody production, cytokine release and antigen presentation to T-cells. The sequence of immune events that trigger AASV are not fully understood, however evidence suggests that ANCA are pathogenic (21). Thus interruption of the cell line leading to ANCA production may be beneficial in disease suppression. Rituximab is an established treatment in non-Hodgkin’s lymphoma with a good safety track record (7). Even though the individual is rendered B cell deplete, immunoglobulin levels are maintained, and infection rates are low. Recently its use in autoimmune diseases has been realised with excellent results in rheumatoid arthritis (8). Rituximab has been shown to be effective in AASV, inducing remission in patients intolerant of cyclophosphamide (5,10-12,22,26-28). Given its good safety profile and efficacy its use a first line agent in AASV needs to be investigated.


In RITUXVAS, a rituximab based regimen will be compared with a standard cyclophosphamide/azathioprine based regimen in the treatment of AASV with glomerulonephritis. In order to achieve results applicable to clinical practice, all cases from mild to severe renal failure will be included. Standard practice includes the use of oral steroids which will be applied similarly in both treatment groups. It is recognised that necrotising cresentic glomerulonephritis progresses rapidly and immediate immune suppression is required to reverse existing and spare further organ damage. The therapeutic effect of rituximab is not immediate. Therefore two initial doses of cyclophosphamide will be given along side rituximab, thus allowing early disease control. When dialysis dependant renal failure or pulmonary haemorrhage occur, plasma exchange or intravenous steroids are standard additional therapies. These will be allowed according to local practice, and randomisation will occur after plasma exchange. Patients in the cyclophosphamide limb will receive azathioprine as remission maintenance therapy. Patients receiving rituximab will not receive any additional maintenance therapy.


1.3. Rituximab

Rituximab is an anti CD 20 chimeric mouse/human monoclonal antibody, with human IgG1 constant regions and murine light/heavy chain variable regions (7). CD 20 is a ligand which exists on developing B cells, excluding stem cells and plasma cells. The role of the CD 20 ligand in nature is not fully understood, although mediation of apoptosis has been suggested. The mechanisms by which rituximab causes B cell depletion may involve complement induced B cell lysis, Fc receptor mediated cytotoxic cell killing or the direct induction of B cell apoptosis by rituximab. Rituximab therapy correlates positively with B cell depletion and rituximab levels. Different dosing regimens have been trialled. In patients with systemic lupus erythematosus (SLE), the efficacy of rituximab is dependant upon B cell depletion. 4 infusions of 375mg/m2 rituximab infusions (one per week for four weeks) were required for this to occur (13,14). In 3 published reports 375mg/m2 has resulted in B cell depletion and clinical response in patients with refractory vasculitis (10-13). On the basis of these results a dose of 4 x 375mg/m2 infusions will be used in RITUXVAS. In RITUXVAS, 2 doses cyclophosphamide will still be administered with the 1st and 3rd rituximab infusions, for two reasons. Firstly, the necrotising cresentic glomerulonephritis associated with AASV progresses rapidly and the therapeutic effect of rituximab is delayed. The use of cyclophosphamide/high dose steroid, which are standard components of induction therapy, will allow adequate immunosuppression in the early crucial treatment of AASV. Secondly, human antichimeric antibody (HACA) formation has been reported in NHL, SLE, and RA with varying frequencies, (4.3% of patients in RA (8)). The long term implications of these antibodies are not known. However, the possibility of anaphylactic reactions and rituximab resistance with further treatments exists. Co-administration of an immunosuppressant effective in the treatment of vasculitis is thus a logical approach to minimise HACA development. Rituximab has now been used to treat 300,000 patients with NHL. Long-term safety regarding carcinogenicity and fertility has yet to be established. However, no major long-term adverse sequelae have been reported (1). Up to 50% of patients receiving rituximab for an indication will develop infusion reactions with symptoms including; fevers, chills, rigors, flushing, throat irritation RITUXVAS EUVAS Trial 9
EUDRACT 2005-003610-15 rash rhinitis fatigue headache, nausea, vomiting, urticaria, angioedema, bronchospasm, myalgia, arthralgia, hypotension, hypertension and exacerbation of angina or congestive cardiac failure. Later reactions include diarrhoea, leucopenia, neutropenia, thrombocytopenia, anaemia, and infections in 30%, which may or may not be drug related (investigators brochure).


1.4. Aims of RITUXVAS:

1 To assess the rates of preliminary response and sustained remission of AASV following rituximab (on the basis of former studies, 86% sustained remission expected with rituximab compared to 75% in control group). 2 To assess safety of a rituximab regimen in terms of severe adverse events (in patients receiving standard therapies, adverse advent rate is 45% at 2 years, at least 50% of which are infection relapted. In comparison rituximab use is only rarely associated with infections, therefore 22.5% adverse event rate expected with rituximab compared to 45% at 2 years in control group).


2. Hypothesis: Rituximab leads to a higher rate of sustained remission compared to standard therapies (cyclophosphamide/azathioprine) with a lower rate of severe adverse events and reduced cyclophosphamide exposure.


3. Trial Design

International, randomised, controlled, prospective, open trial comparing a rituximab based regimen with a standard cyclophosphamide/azathioprine regimen in the treatment of active ‘generalised’ AASV. Informed consent and ethics committee approval will be obtained.


3.1. Inclusion Criteria (all four must be present)

1. A new diagnosis of WG, MP or renal-limited vasculitis (RLV)(appendix 1) 2. Renal involvement attributable to active WG, MP or RLV with at least one of the following: a) Biopsy demonstrating necrotizing glomerulonephritis. b) Red cell casts on urine microscopy or ≥ ++ haematuria 3. ANCA positivity ANCA positivity requires either (a) or (b) (a) PR3-ANCA by ELISA or a typical cANCA pattern by indirect immunofluorescence (IIF), or both. (b) MPO-ANCA by ELISA. A positive pANCA by IIF requires confirmation by MPO-ANCA ELISA.



3.2. Exclusion Criteria

1. Previous cyclophosphamide, (greater than 2 weeks of an oral or IV pulse cyclophosphamide regimen). 2. Co-existence of another multisystem autoimmune disease, e.g. SLE, Churg Strauss Syndrome, Henoch Schonlein Purpura, rheumatoid vasculitis, essential mixed cryoglobulinaemia, anti-glomerular basement membrane antibody positivity 3. Hepatitis B e antigen positive or Hepatitis C antibody positive. 4. Known HIV positive (HIV testing will not be a requirement for this trial). 5. Previous malignancy (usually exclude unless agreed with trial co-ordinator). 6. Pregnancy, breast feeding or inadequate contraception if female. 7 Allergy to a study medication 8 Live Vaccine within last 4 weeks



3.3. Randomisation

1 Variables known to influence primary end points will be balanced between groups by minimisation i Age ii Disease WG or MP/RLV iii Creatinine 2 Randomisation form (see TMF) sent by e-mail rbjones@doctors.org.uk or fax to 01223 586506 (clinical trials office).

3.4. Endpoints Primary end points will be assessed upon trial completion at 2 years. However interim analyses will be performed when 1 30 patients have completed 6 weeks, to assess efficacy (treatment response) and safety (severe adverse events). 2 40 patients have completed 6 months to assess efficacy (remission rates) and safety (severe adverse events).

i Primary

1 Sustained remission (BVAS = 0 at 6 months and sustained for 6 months). 2 Severe adverse events (CTCAE grade ≥ 3) at 2 years.

ii Secondary 1 Efficacy

Response rate at 6 weeks (BVAS < 50% baseline) Remission at 6 months (BVAS=0 for 2 months by 6 months) Time to remission (BVAS=0) Relapses (all relapses and major/minor) BVAS area under the curve Change in GFR Change in SF-36 Change in VDI

2. Safety Severe adverse events (CTCAE grade ≥ 3) at 6 weeks and 6 months

All adverse events Death Prednisolone cumulative dose Cyclophosphamide cumulative dose

iii Tertiary

Human anti-chimeric antibody testing Correlation of B cells with disease activity Change in ANCA and disease activity Histopathology predictors of outcome



3.5. Interventions

I Drug regimens a) Rituximab Regimen: Rituximab, 375mg/m2 IV once a week for 4 weeks (i.e. 4 doses total), with 2 doses of cyclophosphamide 15mg/kg, 2 weeks apart given with the 1st and 3rd rituximab dose (appendix 3).

b) Control (cyclophosphamide/azathioprine) Regimen; Cyclophosphamide 15mg/kg for 3-6 months (6-10 doses total) to be given IV according to protocol (appendix 3) for remission induction. Cyclophosphamide should be converted to azathioprine for remission maintenance. c) Steroids. All patients will receive 1g IV methylprednisolone, then same daily oral corticosteroid regimen (appendix 3). d) Plasma exchange or IV methylprednisolone will be allowed according to local practice for patients with organ threatening disease. NB randomisation should not occur until completion of plasma exchange to avoid loss of rituximab during plasma exchange. The first dose of cyclophosphamide can be given prior to completion of plasma exchange. e) Progressive disease Within the first 6 months disease progression defined as a persistence of nephritic sediment or activity on a renal biopsy and a failure to improve GFR≥ 10 mls/min, if GFR at diagnosis is < 50 mls/min (calculated by cockcroft gault formula, see TMF for formula) OR persistence or new occurrence of a major non-renal BVAS item at 6 weeks then additional treatment should occur: i) Rituximab limb: 3rd dose of cyclophosphamide (15mg/kg) ii) Cyclophosphamide limb: Plasma exchange or IV methylprednisolone (according to local practice). f) Relapse Therapy. Relapses will be categorised as major or minor.

i) Rituximab limb: Rituximab with steroid will be used for major and minor relapse. Additional cyclophosphamide may also be used for major relapse.

ii) Control limb: Increased azathioprine and steroid for minor relapse and cyclophosphamide and steroid for major relapse.

II Evaluations Study assessments (including history and examination) will be performed at entry, 1.5, 3, 6, 9, 12, 15, 18, 21 and 24 months and at the time of relapse (see appendix 5, and TMF for assessment schedule). At each assessment the following should be performed: a) Blood for routine testing. b) 10 mls serum saved for centralised immunological analysis (including ANCA) and HACA. c) BVAS for each assessment and at relapse;

Every 6 months SF-36 and VDI should be performed (23-25)(see TMF).

Initial Renal histology will be reviewed by a EUVAS panel of histopathologists, based in Milan.



3.6. Withdrawal and treatment failure

1 At patient's or physician's request. Reason for withdrawal is to be recorded in the CRF. 2 Patients not achieving remission within 6 months to be withdrawn from trial drug regimen and will be treated according to local practice. They will remain under trial follow up.


3.7. Adverse events

1 Adverse effects will be actively sought and recorded in CRFs at each evaluation (see section 4.5 and TMF). 2 Unexpected, severe adverse events attributable to study medication must be reported within 24 hours to trial management committee. (see TMF and section 4.5 for full details).


3.8. Statistical analysis

Primary end points will be assessed upon trial completion at 2 years. However interim analyses will be performed: (a) When 30 patients have completed 6 weeks trial participation to assess (1) treatment response (BVAS fall of > 50% baseline). (2) safety (adverse events CTCAE grade 3 or greater) and (b) When 40 patients have completed 6 months trial participation to assess (1) remission (BVAS 0 for 2 months by 6 months) (2) safety (adverse events CTCAE grade 3 or greater)Primary end point confidence Intervals. A total of 30 patients will receive rituximab. The expected sustained remission rate for rituximab is 86%, based on the results of former studies. The 95% confidence interval for a sustained remission rate of 86% is 70.3%-94.7% when the sample size is 30. The expected response rate of 86% is considered clinically significant as patients with active newly diagnosed generalised AASV without 3-6 months of cyclophosphamide are conventionally expected to experience disease progression (worsening of clinical signs and symptoms). The expected sustained remission rate in the control group is 75%. Analyses on the 40 patients should be considered exploratory.


3.9. Duration: 3 years: 6 months recruitment, two year follow-up per patient and 6 month analyses.


Visit the EUVAS website for details.