Phase II Study on Gusperimus in Patients With Refractory Wegener's Granulomatosis

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 Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status.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 Overview

• Status: Completed
• Conditions: Wegener's Granulomatosis
• Intervention / Treatment: Drug: Gusperimus

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czech Republic
  • Prague, Czech Republic, 12808
    • General Faculty Hospital
• Denmark
  • Copenhagen, Denmark, 2100
    • Reumatologisk Klinik
• Germany
  • Luebeck, Germany, 23538
    • Universitätsklinikum Schleswig-Holstein
• Netherlands
  • Maastricht, Netherlands, 6202
    • University Hospital Maastricht
• Sweden
  • Stockholm, Sweden, 14186
    • Karolinska University Hospital
• United Kingdom
  • Cambridge, United Kingdom, CB2 2QQ
    • Addenbrookes Hospital
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Western General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; Gusperimus	Drug: Gusperimus; SC, 0.5mg/kg/day, consecutive 21 days administration, 1 to 2 weeks rest, 6 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At Entry (Day 1 of Cycle 1), Day 22 of cycles 1-6, up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Clinical Response	Time from Complete Remission or Partial Remission to Relapse.	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.	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	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.	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.	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.	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.	At Entry (Day 1 of Cycle 1), End of treatment period, up to 24 weeks

Collaborators and Investigators

• Sponsor: Nippon Kayaku Co., Ltd.
• Investigators: Principal Investigator: David Jayne, Addenbrookes Hospital

Publications and helpful links

General Publications

• Birck R, Warnatz K, Lorenz HM, Choi M, Haubitz M, Grunke M, Peter HH, Kalden JR, Gobel U, Drexler JM, Hotta O, Nowack R, Van Der Woude FJ. 15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: a six-month open-label trial to evaluate safety and efficacy. J Am Soc Nephrol. 2003 Feb;14(2):440-7. doi: 10.1097/01.asn.0000048716.42876.14.

Helpful Links

• The European Vasculitis Study Group

Study record dates

Study Major Dates

• Study Start: December 1, 2003
• Primary Completion (ACTUAL): February 1, 2006
• Study Completion (ACTUAL): February 1, 2006

Study Registration Dates

• First Submitted: September 14, 2007
• First Submitted That Met QC Criteria: September 14, 2007
• First Posted (ESTIMATE): September 17, 2007

Study Record Updates

• Last Update Posted (ACTUAL): March 6, 2017
• Last Update Submitted That Met QC Criteria: January 16, 2017
• Last Verified: September 1, 2007

More Information

Terms related to this study

• Keywords: Immunosuppression; Vasculitis; Wegener Granulomatosis; Gusperimus
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Lung Diseases; Vasculitis; Lung Diseases, Interstitial; Systemic Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Granulomatosis with Polyangiitis; Hypoglycemic Agents; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antibiotics, Antineoplastic; Radiation-Protective Agents; Gusperimus
• Other Study ID Numbers: 102