Wegener's Granulomatosis
Conditions
Keywords
Wegener Granulomatosis, Vasculitis, Gusperimus, Immunosuppression
Brief summary
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 Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status.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.
Interventions
DRUGGusperimus
SC, 0.5mg/kg/day, consecutive 21 days administration, 1 to 2 weeks rest, 6 cycles
Sponsors
Nippon Kayaku Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of WG according to American College of Rheumatology (ACR) and Chapel Hill Consensus Conference (CHCC) definition * BVAS \>= 4 * Total disease duration \>= 3 months treated with CYC or \>= 6 months with MTX * Age 18 - 80 * WBC \>= 4,000/mm3, haemoglobin \>= 8g/dl, neutrophils \>= 2,500/mm3, platelets \>= 100,000/mm3 * ALT, bilirubin and alkaline phosphatase levels within 2x the upper limits of normal * Documented to be non-pregnant by serum/urine pregnancy test * Willing to participate in this study * Provide signed informed consent * Able and prepared to self-administer the study drug or have a close friend/relative able to do this
Exclusion criteria
* Participation in another clinical research study * Pregnant or nursing mothers and women of childbearing age not using appropriate contraception * Clear evidence of active disease due to bacteria/viral infection * Patient has an unacceptable risk for participation in a study of immunosuppressive therapy * History of substance abuse or psychotic disorders * Previous treatment with Gusperimus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Remission of Vasculitis | At Entry (Day 1 of Cycle 1), Day 22 of cycles 1-6, up to 24 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Haematuria | At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks | Assessment of anti-inflammatory activity of gusperimus using surrogate marker: number of hematuria-positive patients. |
| Creatinine | At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks | Assessment of anti-inflammatory activity of gusperimus using surrogate marker: serum creatinine level |
| ANCA | At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks | 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. |
| Duration of Clinical Response | 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 | Time from Complete Remission or Partial Remission to Relapse. |
| Vasculitis Damage Index (VDI) | At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks, 6 months of follow-up period | 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. |
| SF-36 | At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks | 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. |
| CRP | At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks | Assessment of anti-inflammatory activity of gusperimus using surrogate marker: serum C-reactive protein level. |
Countries
Czechia, Denmark, Germany, Netherlands, Sweden, United Kingdom
Participant flow
Recruitment details
The study was conducted at 7 sites in 6 European countries from 2003 to 2006
Participants by arm
| Arm | Count |
|---|---|
| Gusperimus SC, 0.5mg/kg/day, consecutive 21 days administration, 7 days rest, 6 cycles | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Lack of Efficacy | 3 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Gusperimus |
|---|---|
| Age, Continuous | 51 Years |
| Gender Female | 16 Participants |
| Gender Male | 29 Participants |
| Region of Enrollment Europe | 45 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 45 / 45 |
| serious Total, serious adverse events | 17 / 45 |
Outcome results
Primary
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
Population: Efficacy Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gusperimus | Remission of Vasculitis | 95 Percentage of participants |
Secondary
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
Population: Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gusperimus | ANCA | At Entry | 39 Number of participants |
| Gusperimus | ANCA | End of treatment period | 34 Number of participants |
Secondary
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
Population: Efficacy population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gusperimus | Creatinine | At Entry | 130 micromol/L |
| Gusperimus | Creatinine | End of treatment period | 132 micromol/L |
Secondary
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
Population: Patients who had elevated CRP level (\> 6 mg/dL) at entry
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gusperimus | CRP | At Entry | 17.5 mg/dL |
| Gusperimus | CRP | End of treatment period | 9 mg/dL |
Secondary
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
Population: Patients who had relapsed after achieved at least partial remission
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gusperimus | Duration of Clinical Response | 170 Days |
Secondary
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
Population: Efficacy population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gusperimus | Haematuria | End of treatment period | 6 Number of participants |
| Gusperimus | Haematuria | At Entry | 16 Number of participants |
Secondary
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
Population: Efficacy Population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gusperimus | SF-36 | Physical component score (at Entry) | 29.6 Score on a scale |
| Gusperimus | SF-36 | Physical component score (at End of treatment peri | 34.3 Score on a scale |
| Gusperimus | SF-36 | Mental component score (at Entry) | 49.4 Score on a scale |
| Gusperimus | SF-36 | Mental component score (at End of treatment period | 48 Score on a scale |
Secondary
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
Population: Efficacy Population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gusperimus | Vasculitis Damage Index (VDI) | At Entry | 4.5 Score on a scale |
| Gusperimus | Vasculitis Damage Index (VDI) | End of treatment period | 5 Score on a scale |
| Gusperimus | Vasculitis Damage Index (VDI) | 6 months of follow-up period | 5 Score on a scale |