| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapse of Wegener?s Granulomatosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| new onset of the activity of Wegener?s Granulomatosis |
|
| 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 | 14.0 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| 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 |
|
| 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). |
| El propósito del estudio es evaluar la eficacia (ensayo de superioridad) de gusperimus comparado con el tratamiento convencional en pacientes con recurrencia de GW, con o sin glucocorticoides en curso y/o terapia inmunosupresora (AZA, MMF, MTX o LEF). |
|
| 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. |
Evaluar la seguridad y calidad de vida del tratamiento gusperimus comparado con el tratamiento estándar en pacientes con recurrencia de GW recibiendo GC.
Los parámetros farmacocinéticos:
? Evaluar la farmacocinética de gusperimus S.C. en ésta población de pacientes
? Evaluar la variabilidad entre ? intra sujetos en la farmacocinética de gusperimus tras la administración crónica S.C. |
|
| 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. |
Los parámetros farmacocinéticos obtenidos durante 3 ciclos diferentes en una parte restringida de la población de pacientes (35 pacientes tratados con gusperimus) se evaluarán por los siguientes criterios:
? Evaluar la farmacocinética de gusperimus S.C. en ésta población de pacientes
? Evaluar la variabilidad entre ? intra sujetos en la farmacocinética de gusperimus tras la administración crónica S.C. |
|
| 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. |
1. Diagnóstico documentado de GW de acuerdo a los criterios de clasificación del ACR.
2. Diagnóstico de GW al menos 6 meses antes de ingresar e iniciar la terapia de inducción con la combinación de GC y un inmunosupresor (CYC o MTX) o rituximab.
3. Recurrencia de GW con o sin curso de GC, y/o terapia inmunosupresora con AZA/MMF/MTX o LEF. La mínima actividad de enfermedad está definida por la presencia de un ítem mayor nuevo/empeoramiento o tres ítems menores nuevo/empeoramiento en BVAS (versión 3).
4. Pacientes entre 18 -75 años.
5. Método anticonceptivo médicamente aceptado y confiable durante el curso del estudio.
(Las mujeres no deben quedar embarazadas hasta al menos 6 meses después del tratamiento con CYC)
6. Consentimiento Informado por escrito dado por el paciente para la participación en el estudio.
7. Pacientes capaces y preparados para auto-administrarse la medicación en estudio o tener un pariente/tercera persona capaz de hacerlo.
8. Capacidad de leer, entender y registrar la información requerida por el protocolo. |
|
| 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. |
1. Otros desórdenes autoinmunes multi-sistémicos, incluyendo lupus eritematoso y enfermedad anti-GBM.
2. Vasculitis Sistémica debida a infección viral.
3. Intolerancia a la terapia con CYC, hipersensibilidad o contraindicación a CYC (sustancia activa o algún excipiente) en pacientes con recurrencia grave de GW.
4. Hipersensibilidad o contraindicación a
- Spanidin (sustancia activa o algún excipiente) o
- MTX (sustancia activa o algún excipiente) y AZA(sustancia activa o algún excipiente) o
- Metilprednisolona, prednisolona u otro corticosteroide (sustancia activa o algún excipiente).
5. Condiciones médicas subyacentes, que en opinión del Investigador pongan al paciente en un nivel de riesgo inaceptable por participar en el estudio.
6. Previa aleatorización en éste estudio.
7. La CYC, inmunoglobulina intravenosa, terapias biológicas anticitoquinas, intercambio de plasma o Abatacept en los tres meses previos al ingreso en el ensayo. Rituximab, Alemtuzumab o el trasplante de células madre no están permitidos en los seis meses previos al ingreso en el ensayo.
8. Previo tratamiento con gusperimus.
9. Participación en otro ensayo clínico con fármacos en investigación en los últimos 3 meses antes del screening o durante el presente periodo del ensayo.
10. Mujeres embarazadas o lactantes.
11. Infección bacteriana/viral activa (VIH, Hepatitis B, Hepatitis C, Tuberculosis).
12. Pacientes con eGFR < 15 mL/min/1.73 m2 (ecuación MDRD).
13. Niveles de ALT, AST, bilirrubina, y fosfatasa alcalina 2x por encima del límite normal superior.
14. Inadecuada función de la medula ósea: leucocitos < 4000/mm3, hemoglobina < 8 g/dL, neutrófilos < 2500/mm3, plaquetas < 100 000/mm3. |
|
| 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). |
| La variable de eficacia principal es el porcentaje de pacientes que muestran, dentro de las 24 semanas de ingresar en el ensayo, respuesta con el nivel de actividad de la enfermedad BVAS ? 2, el cual se mantiene sin recurrencias hasta el final del ensayo (al final de la semana 52) |
|
| 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 |
Alcanzar un BVAS ? 2 dentro de las 24 semanas
Mantenimiento de un BVAS ? 2 hasta el final de la semana 52 |
|
| 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. |
- Tiempo de respuesta (respuesta es definida como el tiempo desde el ingreso en el estudio hasta la primera ocasión cuando el BVAS es ? 2, y ha habido adherencia al protocolo de reducción de esteroides).
- Duración de la respuesta definida como el tiempo desde la respuesta con BVAS ? 2 hasta una recurrencia (recurrencia es definida como el retorno o primera aparición de un ítem mayor y/o tres ítem menores BVAS).
- Frecuencia de recurrencias graves (definido como al menos un ítem mayor BVAS).
- Frecuencia de recurrencias no-graves (definido como al menos 3 ítems menores BVAS sin ítems mayores BVAS).
- Cambio en el puntaje VDI desde el basal hasta el mes 12.
- Cambio en el eGFR desde el basal hasta el mes 12 en todos los pacientes y en un subgrupo definido como tener un basal de GFR < 60 mL/min (ej. Insuficiencia renal en el basal).
- Frecuencia de AAs y AAGs. (Total número de AAs por grupo de acuerdo a la categoría de AA) (Porcentaje de pacientes en cada grupo con un AA grave)
- Frecuencia de infecciones graves (una infección grave es definida como una infección que requiere antibióticos intravenosos u hospitalización). Porcentaje de pacientes en cada grupo con una infección grave.
- Parámetros farmacocinéticos AUC, Cmax, Tmax y T ½ calculados a partir de las muestras de plasma recogidas en intervalos de tiempo regulares después de la administración de gusperimus el primer día de tres ciclos de tratamiento.
- Cambio en los dominios mentales y físicos del SF-36 agrupados desde el basal hasta el mes 6.
- Cambio en los dominios mentales y físicos del SF-36 agrupados desde el basal hasta el mes 12.
- La exposición total a corticosteroides.
- Cambio en EQ5D desde el basal y el mes 12. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| please see E.5.2 |
| Por favor ver E.5.2 |
|
| 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 |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 |
|
| 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
|
|
| 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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