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

• ClinicalTrials.gov Identifier: NCT00530075
• Recruitment Status: Completed
• First Posted: September 17, 2007
• Results First Posted: March 6, 2017
• Last Update Posted: March 6, 2017
• Sponsor: Nippon Kayaku Co., Ltd.
• Information provided by: Nippon Kayaku Co., Ltd.

Study Description

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 Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status.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

Condition or disease	Intervention/treatment	Phase
Wegener's Granulomatosis	Drug: Gusperimus	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study on Gusperimus in Patients With Refractory Wegener's Granulomatosis
• Study Start Date: December 2003
• Actual Primary Completion Date: February 2006
• Actual Study Completion Date: February 2006

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Remission of Vasculitis [ Time Frame: 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 Outcome Measures :

1. Duration of Clinical Response [ 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 ]
   Time from Complete Remission or Partial Remission to Relapse.
2. Haematuria [ Time Frame: 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.
3. Creatinine [ Time Frame: 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
4. ANCA [ Time Frame: 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.

5. CRP [ Time Frame: 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.
6. Vasculitis Damage Index (VDI) [ Time Frame: 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.
7. SF-36 [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Czech Republic

General Faculty Hospital

Prague, Czech Republic, 12808

Denmark

Reumatologisk Klinik

Copenhagen, Denmark, 2100

Germany

Universitatsklinikum Schleswig-Holstein

Luebeck, Germany, 23538

Netherlands

University Hospital Maastricht

Maastricht, Netherlands, 6202

Sweden

Karolinska University Hospital

Stockholm, Sweden, 14186

United Kingdom

Western General Hospital

Edinburgh, Scotland, United Kingdom, EH4 2XU

Addenbrookes Hospital

Cambridge, United Kingdom, CB2 2QQ

Sponsors and Collaborators

Nippon Kayaku Co., Ltd.

Investigators

• Principal Investigator: David Jayne; Addenbrookes Hospital

More Information

Additional Information:

The European Vasculitis Study Group 

Publications:

Birck R, Warnatz K, Lorenz HM, Choi M, Haubitz M, Grünke M, Peter HH, Kalden JR, Göbel 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.

• Responsible Party: Peter A. Heinzel, Ph.D., Clinical and Scientific Department, Euro Nippon Kayaku GmbH
• ClinicalTrials.gov Identifier: NCT00530075
• Other Study ID Numbers: 102
• First Posted: September 17, 2007
• Results First Posted: March 6, 2017
• Last Update Posted: March 6, 2017
• Last Verified: September 2007

Keywords provided by Nippon Kayaku Co., Ltd.:

Wegener Granulomatosis; Vasculitis; Gusperimus; Immunosuppression

Additional relevant MeSH terms:

Granulomatosis with Polyangiitis; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Systemic Vasculitis; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Autoimmune Diseases; Immune System Diseases; Gusperimus; Antibiotics, Antineoplastic; Antineoplastic Agents; Hypoglycemic Agents; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Radiation-Protective Agents; Protective Agents