Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 2011-001219-30 | EudraCT Number |
Not provided
Not provided
Change of design consideration
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The aim of the study is to assess the efficacy (superiority testing) of gusperimus compared to conventional treatment in patients with a relapse of Wegener Granulomatosis with or without ongoing steroids, and/or immunosuppressive therapy. Further, to evaluate the safety and quality of life of gusperimus treatment compared to standard treatment in patients with relapse of Wegener Granulomatosis receiving glucocorticoids.
Wegener Granulomatosis without treatment is life-threatening. The standard treatment with corticosteroids and cyclophosphamide is usually effective at controlling active disease. However, disease relapse is frequent and requires increased exposure to these toxic drugs. In other patients initiation or continuation of these standard drugs is contraindicated due to intolerable side effects. No well-established therapy is available for relapsing patients. They may suffer severe organ damage due to progressive disease, or may die. The proposed indication for gusperimus is the treatment of relapsing Wegener Granulomatosis. The aim of therapy with gusperimus is to induce and maintain remission thereby avoiding further cyclophosphamide and reducing corticosteroid exposure.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Test group - gusperimus | Experimental | Both severity subgroups (severe and non-severe) will be treated with gusperimus + glucocorticoids. |
|
| Control group | Active Comparator | The severe subgroup will receive a course (13 - 22 weeks) of cyclophosphamide followed by methotrexate + glucocorticoids. Patients intolerant to methotrexate and patients with impaired renal function will receive azathioprine + glucocorticoids. The non-severe subgroup will receive methotrexate + glucocorticoids(or azathioprine + glucocorticoids for those previously intolerant to methotrexate or with impaired renal function). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Gusperimus + glucocorticoids | Drug | Both severity subgroups will be treated with gusperimus + glucocorticoids up to 12 months. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Response rate | The primary efficacy variable is the rate of patients showing a response, with the level of disease activity Birmingham Vasculitis Activity Score (BVAS) ≤ 2, within 24 weeks of trial entry, which is maintained without relapse until the end of the trial (Week 52). The primary efficacy endpoint includes: i) Remission - defined as the complete absence of active clinical disease, i.e. a BVAS score of 0, for at least two months on a stable prednisone dose of ≤ 10 mg/day. ii) Low activity Disease State - persistence of up to two minor BVAS items (BVAS ≤ 2). | 52 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Time to response | Time to response (response is defined as the time from study entry to the first occasion that BVAS is ≤ 2, and there has been adherence to the steroid reduction protocol) | From the date of study entry until the first occasion that BVAS is ≤ 2, assessed up to 52 weeks |
| Response duration |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Other multi-system autoimmune disorders, including systemic lupus erythematosus and anti-Glomerular Basement Membrane disease.
Systemic vasculitis due to a viral infection.
Cyclophosphamide therapy intolerance, hypersensitivity or contraindication to Cyclophosphamide (active substance or any of the excipients) in patients with severe relapse of WG.
Hypersensitivity or contraindication to
Underlying medical conditions, which in the opinion of the Investigator place the patient at an unacceptable risk level for participating in a study.
Previous randomisation in this study.
Cyclophosphamide , intravenous immunoglobulin, anti-cytokine biologic therapies, plasma exchange or Abatacept in the three months prior to entry to the trial. Rituximab, Alemtuzumab or stem cell transplantation is not permitted in the six months prior to entry to the trial.
Previous treatment with gusperimus.
Participation in another clinical trial with investigational drugs within the last 3 months before screening or during the present trial period.
Pregnant or breast-feeding females.
Active bacterial/viral infection (Human Immunodeficiency Virus, Hepatitis B, Hepatitis C, Tuberculosis).
Patients with Glomerular Filtration Rate (eGFR) < 15 mL/min/1.73m2.
Alanine transaminase (ALT), Aspartate aminotransferase (AST), bilirubin, and Alkaline phosphatase (ALP) levels above 2 x the upper normal limit.
Inadequate bone-marrow function: White Blood Cells (WBC) < 4000/mm3, haemoglobin < 8 g/dL, neutrophils < 2500/mm3, platelets < 100 000/mm3.
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| David Jayne, MD | Addenbrookes Hospital, Cambridge, United Kingdom | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Všeobecná fakultní nemocnice v Praze | Prague | 128 08 | Czechia |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| cyclophosphamide followed by methotrexate (azathioprine) + glucocorticoids or methotrexate (azathioprine) + glucocorticoids | Drug | Severe subgroup: will receive intravenous cyclophosphamide pulses for at least 13 weeks and 22 weeks at maximum, followed by methotrexate + glucocorticoids after achieving a response with BVAS ≤ 2. Patients intolerant to methotrexate and patients with impaired renal function will receive azathioprine + glucocorticoids . Non-severe subgroup: will receive methotrexate + glucocorticoids (or azathioprine + glucocorticoids for those previously intolerant to methotrexate or with impaired renal function). |
|
Response duration defined as time from response with BVAS≤2 to relapse (relapse is defined as the return or first occurrence of one major and/or three minor BVAS items) |
| From the date of response with BVAS≤2 until relapse, assessed up to 48 weeks |
| Frequency of severe relapses | Frequency of severe relapses (defined as at least one major BVAS item) | Up to 52 weeks |
| Vasculitis Damage Index (VDI) score change | VDI score change from baseline to month 12 | 12 months |
| Glomerular Filtration Rate (eGFR) change | eGFR change from baseline to month 12 in all patients and in a subgroup defined as having a baseline eGFR ≤ 60mL/min (i.e. renal impairment at baseline) | 12 months |
| Frequency of Adverse Events (AEs) and Serious Adverse Event (SAEs) | Frequency of AEs and SAEs. (Total number of AEs per group according to AE category) (Percentage of patients in each group with a severe AE) | Up to 52 weeks |
| Frequency of severe infection | Frequency of severe infection (a severe infection is defined as an infection that requires intravenous antibiotics or hospitalisation).(Percentage of patients in each group with a severe infection) | Up to 52 weeks |
| Pharmacokinetic parameters at selected sites | Pharmacokinetic parameters Area Under the plasmaconcentration - time Curve (AUC), Maximum concentration reached in plasma (Cmax), Time to maximum concentration reached in plasma (Tmax) and Elimination half life in plasma (T½) calculated from the measured plasma samples collected at regular time intervals after administration of gusperimus on the first day of three treatment cycles | 1st day of gusperimus cycles 1, 6 or 7, 12 or 13 |
| Short-Form-36 (SF-36) | Pooled physical and mental SF-36 domains change from baseline to month 6 | 6 months |
| Short-Form-36 (SF-36) | Pooled physical and mental SF-36 domains change from baseline to month 12 | 12 months |
| Total corticosteroid exposure | The total corticosteroid exposure | Up to 52 weeks |
| Questionnaire EQ-5D | Change in EQ-5D between baseline and month 12 | 12 months |
| Frequency of non-severe relapses | Frequency of non-severe relapses (defined as at least 3 minor BVAS items with no major BVAS items). | Up to 52 weeks |
| ID | Term |
|---|---|
| D014890 | Granulomatosis with Polyangiitis |
| D012008 | Recurrence |
| ID | Term |
|---|---|
| D017563 | Lung Diseases, Interstitial |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D056648 | Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis |
| D056647 | Systemic Vasculitis |
| D014657 | Vasculitis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| C037258 | gusperimus |
| D005938 | Glucocorticoids |
| D001379 | Azathioprine |
| D008727 | Methotrexate |
| ID | Term |
|---|---|
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045505 | Physiological Effects of Drugs |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D013872 | Thionucleosides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D015122 | Mercaptopurine |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
Not provided
Not provided