ALEmtuzumab for relapsing and refractory primary systemic VasculitIs – a Trial of Efficacy and safety

Research summary

Granulomatosis with polyangiitis (GPA) (formerly Wegner’s granulomatosis), microscopic polyangiitis (MPA) and eosininophilic granulomatosis with polyangiitis (eGPA) (formerly Churg Strauss Syndrome (CSS)) are primary systemic vasculitides, predominantly involving microscopic blood vessels with no or scanty immune deposits. Their association with circulating autoantibodies to neutrophils (ANCA) has led to these conditions being grouped together as ANCA associated vasculitis (AAV). The cause of AAV is unknown. AAV has an annual incidence of 20 per million and an approximate prevalence of 200/million. It is a multi-system autoimmune disease that causes tissue damage especially to the respiratory tract and kidneys and causes early mortality, organ failure including end-stage renal disease, and chronic morbidity.

Prior to the availability of effective treatment, AAV was almost universally fatal, with a 93% mortality within 2 years due to pulmonary and renal failure. The introduction of what is now termed conventional immunosuppressive treatment transformed survival. Administration of cytotoxic immunosuppression (cyclophosphamide or methotrexate) and corticosteroids for at least one year induces remission in approximately 80% of patients. However, there are a significant proportion of patients that inadequately respond to traditional therapy. Also, relapsing disease is common with over 50% of patients experiencing a relapse within 5 years. Relapse is associated with increased exposure to immunosuppressive medications and corticosteroids and at least 25% suffer severe early or late toxicity from these agents.

Eosinophilic granulomatosis with polyangiitis (eGPA) is often considered a form of AAV, although the presence of ANCA is not universal. As for GPA and MPA, standard induction immunosuppressive treatment is with glucocorticoids and cyclophosphamide for those with adverse prognostic features. Current maintenance strategies are as for GPA and MPA, although relapses are common, necessitating further treatment.

Behçet’s disease (BD) is a chronic relapsing inflammatory disease, of unknown aetiology, characterised by recurrent oral and genital apthous ulceration, with numerous other potential systemic vasculitic manifestations, the most serious of which include neurological, gastrointestinal and vascular involvement. BD lacks pathognomonic symptoms, laboratory and histological findings, and so diagnosis relies on clinical criteria. The most widely accepted are those of the International Study Group for Behçet’s Disease (ISGBD). Oral ulceration is mandatory, with the presence of at least two of the following: recurrent genital ulceration, eye lesions, skin lesions or a positive pathergy test, to make the diagnosis. More recently the International Criteria for Behcet’s disease (ICBD) was developed and includes vascular manifestations in addition to the five criteria of the ISGBD. As with AAV, involvement of multiple organs is observed in BD, and a perivasculitis, with neutrophil infiltration, endothelial cell swelling and fibrinoid necrosis can be seen on tissue histology. BD was formerly added to the Nomenclature of Vasculitides at the 2012 Chapel Hill Consensus Conference to reflect the view that it is a primary vasculitis, rather than a systemic disease with vasculitic manifestations.

There is a major unmet need for safer therapy that leads to sustained treatment-free remission in patients with relapsing or refractory disease, which will reduce drug toxicity that results from cumulative exposure to cyclophosphamide and glucocorticoids. ALEVIATE is an open-label efficacy/safety randomized study to assess the disease response and SAE rates. The patient subgroup has been selected due to the high unmet need for relapsing and refractory PSV and the results of previous experience in vasculitis outlining those patients most at risk from this intervention who are excluded. The dosage has been selected following experience in multiple sclerosis, a related autoimmune disease, where a 60mg dose was effective. Exploration of lower doses will permit the identification of a dose response association for both efficacy and safety.

ALEVIATE aims to determine the clinical response and severe adverse event rates associated with alemtuzumab therapy among patients with relapsing or refractory primary systemic vasculitis (PSV), by investigating whether treatment with alemtuzumab induces sustained remission in PSV and will reduce immunosuppressive and steroid exposure. The trial objectives are to assess the efficacy (vasculitis response at 6 months) and safety (proportion of patients with severe adverse events) of alemtuzumab in refractory or relapsing PSV.

Main inclusion criteria

A total of 24 subjects, both male and female, with refractory or relapsing PSV will be treated in this study. Subjects must meet all of the following criteria to be eligible for enrolment.

  1. A diagnosis of one of the following primary systemic vasculitides – granulomatosis with polyangitiis (GPA) (formerly Wegener’s Granulomatosis), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (eGPA) (formerly Churg Strauss Syndrome (CSS)) or Behcet’s disease (see 20.2 for diagnostic criteria)
  2. Active vasculitis with at least one severe or three non severe items of BVAS/WG activity (equivalent to BVAS/WG>3)
  3. Previous induction therapy with either cyclophosphamide or methotrexate or rituximab, in combination with prednisolone for at least 3 months in the case of GPA, MPA or eGPA, OR, at least 6 months of anti-TNF therapy for patients with Behcet’s disease.
  4. Written informed consent

Main exclusion criteria

  1. Age less than 18 or greater than 60 years
  2. Creatinine > 150μmol/l (1.7mg/dl)
  3. Total white count < 4x109/l or lymphocyte count < 0.5x109/l, or IgG < 5g/L, or neutrophil count < 1.5x109/l.
  4. Severe lung haemorrhage with hypoxia (<85% on room air)
  5. Severe gastrointestinal, central nervous system or cardiac vasculitis
  6. Previous therapy with:

    1. Alemtuzumab at any time
    2. IVIg, infliximab, etanercept, adalimumab, abatacept, anti-thymocyte globulin or plasma exchange in past three months
    3. Infliximab, etanercept or adalimumab within the past one month
    4. Rituximab within the past 6 months
  7. Intensive care unit requirement
  8. Active infection with HIV, hepatitis B or hepatitis C or other infection requiring parenteral or long-term oral antibiotics
  9. History of ITP or platelet count at screening below 50,000 x 106/l
  10. Pregnancy or inadequate contraception in pre-menopausal women
  11. Breastf eeding
  12. Any condition judged by the investigator that would cause the study to be detrimental to the patient.
  13. Any other multisystem autoimmune disease including Churg Strauss angiitis, systemic lupus erythematosus, anti-GBM disease and cryoglobulinaemia
  14. Any previous or current history of malignancy (other than resected basal cell carcinoma)

Chief investigator

Prof David Jayne

Contact details

Senior Clinical Trials CoordinatorDr Maria King

Telephone: 01223 596441 | Email: [email protected]