| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapse of Wegener’s Granulomatosis |
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| E.1.1.1 | Medical condition in easily understood language |
| new onset of the activity of Wegener’s Granulomatosis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10047888 |
| E.1.2 | Term | Wegener's granulomatosis |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10047889 |
| E.1.2 | Term | Wegeners granulomatosis |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The aim of the study is to assess the efficacy (superiority testing) of gusperimus compared to conventional treatment in patients with a relapse of WG with or without ongoing steroids, and/or immunosuppressive therapy (AZA/MMF/MTX or LEF).
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and quality of life of gusperimus treatment compared to standard treatment in patients with relapse of WG receiving GC
The pharmacokinetic parameters
- to examine the pharmacokinetics of s.c. gusperimus in this patient population
- to assess inter- and intra- subject variability in gusperimus pharmacokinetics following chronic s.c. administration.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic sub-study:
The pharmacokinetic parameters obtained during 3 different cycles in a restricted part of the patient population (35 gusperimus - treated patients) will be evaluated for the following criteria:
- to examine the pharmacokinetics of s.c. gusperimus in this patient population
- to assess inter- and intra- subject variability in gusperimus pharmacokinetics following chronic s.c. administration.
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| E.3 | Principal inclusion criteria |
1. Documented diagnosis of WG according to the ACR classification criteria.
2. Diagnosis of WG at least 6 months before entry and initial induction therapy with a combination of GC and an immunosuppressive (CYC or MTX) or rituximab.
3. Relapse of WG with or without ongoing GC, and/or immunosuppressive therapy with AZA/MMF/MTX or LEF. The minimum disease activity is defined by the presence of one new/worse major or three new/worse minor BVAS (version 3) items.
4. Patients between 18 – 75 years.
5. Medically acceptable and reliable contraception method during the study course.
(Women should not become pregnant for at least 6 months after CYC treatment).
6. Written informed consent for study participation given by the patient.
7. Patients able and prepared to self-administer the study medication or having a relative/third person able to do it.
8. Ability to read, understand and record information required by protocol. |
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| E.4 | Principal exclusion criteria |
1. Other multi-system autoimmune disorders, including systemic lupus erythematosus and anti-GBM disease.
2. Systemic vasculitis due to a viral infection.
3. CYC therapy intolerance, hypersensitivity or contraindication to CYC (active substance or any of the excipients) in patients with severe relapse of WG.
4. Hypersensitivity or contraindication to
- Spanidin (active substance or any of the excipients) or
- both MTX (active substance or any of the excipients) and AZA (active
substance or any of the excipients) or
- methylprednisolone, prednisolone or other corticosteroids (active substance or any of the excipients).
5. Underlying medical conditions, which in the opinion of the Investigator place the patient at an unacceptable risk level for participating in a study.
6. Previous randomisation in this study.
7. CYC, 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.
8. Previous treatment with gusperimus.
9. Participation in another clinical trial with investigational drugs within the last 3 months before screening or during the present trial period.
10. Pregnant or breast-feeding females.
11. Active bacterial/viral infection (HIV, Hepatitis B, Hepatitis C, Tuberculosis).
12. Patients with eGFR < 15 mL/min/1.73m2 (MDRD equation).
13. ALT, AST, bilirubin, and ALP levels above 2 x the upper normal limit.
14. Inadequate bone-marrow function: WBC < 4000/mm3, haemoglobin < 8 g/dL, neutrophils < 2500/mm3, platelets < 100 000/mm3. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the rate of patients showing, within 24 weeks of trial entry, response with the level of disease activity BVAS ≤ 2 that is maintained without relapse until the end of the trial (Week 52). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Achievement of BVAS ≤ 2 within 24 weeks
Maintenance of BVAS ≤ 2 until the end of 52nd week |
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| E.5.2 | Secondary end point(s) |
- 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).
- 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).
- Frequency of severe relapses (defined as at least one major BVAS item).
- Frequency of non-severe relapses (defined as at least 3 minor BVAS items with no major BVAS items).
- VDI score change from baseline to month 12.
- 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).
- 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).
- 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).
- Pharmacokinetic parameters AUC, Cmax, Tmax and T½ calculated from the measured plasma samples collected at regular time intervals after administration of gusperimus on the first day of three treatment cycles.
- Pooled physical and mental SF 36 domains change from baseline to month 6.
- Pooled physical and mental SF 36 domains change from baseline to month 12.
- The total corticosteroid exposure.
- Change in EQ5D between baseline and month 12.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| France |
| Germany |
| Italy |
| Netherlands |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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