Wegener's granulomatosis is a primary systemic vasculitis characterized by granulomatous and necrotizing inflammation predominantly affecting the respiratory tract and the kidneys. Conventional therapy of Wegener's granulomatosis with cyclophosphamide and corticosteroids is limited by incomplete remissions and a high relapse rate. Patients accumulate irreversible damage due to the disease and the consequences of prolonged drug exposure. The efficacy and safety of an alternative immunosuppressive drug, gusperimus, was evaluated in patients with refractory disease. A prospective, international, nulti-centre, single limb, open label study. Entry required active Wegener's granulomatosis with a Birmingham Vasculitis Activity Score (BVAS) \>=4 and previous therapy with cyclophosphamide or methotrexate. Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status. Gusperimus, 0.5mg/kg/day, was self-administered by subcutaneous injection in six treatment cycles of 21 days with a seven day washout between cycles. Cycles were stopped early for white blood count \< 4,000/mm3. The primary endpoint was complete remission (BVAS=0 for at least 2 months) or partial remission (BVAS\<50% of entry score). After the sixth cycle azathioprine was commenced and follow-up continued for a further six months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
45
SC, 0.5mg/kg/day, consecutive 21 days administration, 1 to 2 weeks rest, 6 cycles
General Faculty Hospital
Prague, Czechia
Reumatologisk Klinik
Copenhagen, Denmark
Universitatsklinikum Schleswig-Holstein
Lübeck, Germany
University Hospital Maastricht
Maastricht, Netherlands
Karolinska University Hospital
Stockholm, Sweden
Western General Hospital
Edinburgh, Scotland, United Kingdom
Addenbrookes Hospital
Cambridge, United Kingdom
Remission of Vasculitis
The primary efficacy outcome measure was remission of vasculitis. Complete remission was defined as a Birmingham vasculitis activity score (BVAS) of 0 sustained for at least 2 months. Partial remission was defined as a reduction in BVAS of 50% or more, sustained for at least 2 months, when compared with the BVAS at entry. Entry required active Wegener's granulomatosis with a BVAS \>= 4. Their disease had to be active, as measured with BVAS in which clinical manifestations caused by active vasculitis are scored on a list of predefined organ-specific items.
Time frame: At Entry (Day 1 of Cycle 1), Day 22 of cycles 1-6, up to 24 weeks
Duration of Clinical Response
Time from Complete Remission or Partial Remission to Relapse.
Time frame: At Entry (Day 1 of Cycle 1), Day 22 of cycles 1-6, up to 24 weeks, End of treatment period, and 3 and 6 months of follow-up period
Haematuria
Assessment of anti-inflammatory activity of gusperimus using surrogate marker: number of hematuria-positive patients.
Time frame: At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks
Creatinine
Assessment of anti-inflammatory activity of gusperimus using surrogate marker: serum creatinine level
Time frame: At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks
ANCA
Assessment of anti-neutrophil cytoplasmic antibody (ANCA): Number of ANCA-positive patients was counted. ANCA are highly associatred with active WG, with c-ANCA titres observed in 90% of WG. In addition to their diagnostic value, it has been suggested that ANCA may have a predictive value for relapse in patients with systemic vasculitis.
Time frame: At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks
CRP
Assessment of anti-inflammatory activity of gusperimus using surrogate marker: serum C-reactive protein level.
Time frame: At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks
Vasculitis Damage Index (VDI)
Assessment of the degree of irreversible damage due to the vasculitis using VDI scoring system. The VDI comprises 64 items of damage (grouped into 11 organ-based systems). Total VDI score is 0 - 64. The higher scores represent the more severe damage occurred in patients. The VDI score can either increase or remain the same over time.
Time frame: At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks, 6 months of follow-up period
SF-36
Assessment of the impact of gusperimus on general health using the Short form-36 (SF-36) questionaire. The SF-36 is a self-report, 36 item survey measuring health-related quality-of-life. Thirty-five items are used to construct 8 scales: (1) physical functioning, (2) role physical, (3) bodily pain, (4) general health, (5) vitality, (6) social function, (7) role emotional, and (8) mental health. Raw scores are calculated as the sum of re-coded scale items and transformed to a 0 to 100 scale. If scores for all 8 scales are available, two summary measures known as component scores are derived: the Physical Health Component Score (PCS) and the Mental Health Component Score (MCS). First each scale standardized to the relevant population. Then PCS and MCS are calculated as the weighted sum of standardized scores. All scales and the component scores are positively scored so that higher scores represent better health-related quality-of-life.
Time frame: At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks
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