| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Giant cell arteritis (GCA) |
| ARTERITIS DE CÉLULAS GIGANTES |
|
| E.1.1.1 | Medical condition in easily understood language |
| An inflammatory disease of the blood vessels that typically occurs in individuals over 50 years of age. It can cause fever, headache, jaw or mouth pain and can lead to irreversible vision loss |
| Enfermedad inflamatoria de los vasos sanguíneos que suele ocurrir en individuos mayores de 50 años. Puede causar: fiebre, dolores de cabeza, de mandíbula o de boca y pérdida de visión irreversible |
|
| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018250 |
| E.1.2 | Term | Giant cell arteritis |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of tocilizumab (TCZ) compared to placebo, in combination with a 26 week prednisone taper regimen, in patients with giant cell arteritis (GCA), as measured by the proportion of patients in sustained remission at Week 52 following induction and adherence to the protocol-defined prednisone taper regimen |
| Evaluar la eficacia del tocilizumab (TCZ) en comparación con un placebo y en combinación con una pauta descendente de prednisona durante 26 semanas en pacientes con arteritis de células gigantes (ACG), midiéndose dicha eficacia por la proporción de pacientes en remisión sostenida en la semana 52 a partir de la inducción y la observancia de la pauta descendente de prednisona definida en el protocolo. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate
?efficacy of TCZ in combination with a 26-wk prednisone taper regimen vs placebo in combination with the 52-wk prednisone taper regimen, in pts with GCA, as measured by the proportion of pts in sustained remission at Wk 52 following induction and adherence to the protocol-defined prednisone taper regimen
?efficacy of TCZ in combination with a 26-wk prednisone taper regimen vs both placebo groups, in pts with GCA, as measured by the following:
?Time to GCA disease flare after clinical remission
?Cumulative CS dose
?effect on pts QoL of TCZ in combination with a 26-wk prednisone taper regimen vs both placebo groups, in pts with GCA, based on the patient-reported outcome as measured by SF-36 and patient global assessment of disease activity on a visual analogue scale
?PK and PD of TCZ in combination with a 26-wk prednisone taper regimen in pts with GCA
?safety, tolerability, immunogenicity of TCZ in combination with a 26-wk prednisone taper regimen in pts with GCA |
Evaluar eficacia de TCZ en combinación con una pauta descendente de prednisona durante 26 semanas, vs placebo en comb. con una pauta descendente de prednisona durante 52 sem, en pac con ACG, medido por pacientes en remisión sostenida en la semana 52 a partir de inducción y adherencia a la pauta descendente de prednisona de acuerdo al protocolo. Valorar eficacia de TCZ en combinación con una pauta descendente de prednisona de 26 semanas vs ambos grupos de placebo, en pacientes con ACG, medida en función de:
Tiempo hasta un brote de ACG tras remisión clínica.Dosis corticosteroide acumulada. Evaluar el efecto de TCZ combinado con una pauta descendente de prednisona de 26 sem vs ambos grupos de placebo, en pacientes con ACG, sobre la calidad de vida del paciente, basándose en el RNP y el SF-36 y la evaluación global de la PGA sobre una EAV. Valorar la FC, FD, seguridad, torelabilidad, inmunogenicidad de TCZ en combinación con pauta descendente de prednisona de 26 sem en pacientes con ACG |
|
| 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 Substudy to assess the PK of TCZ in GCA patients.
This substudy is planned to be conducted at selected sites (see protocol WA28119, section 3.1.1.7 and section 3.4.4) |
| Subestudio de farmacocinetica para evaluar el PK DE TCZ en pacientes GCA. Este subestudio es planificado para ser conducido en sitios seleccionados (mirar el protocolo WA28119, la sección 3.1.1.7 y la sección 3.4.4) |
|
| E.3 | Principal inclusion criteria |
Diagnosis of GCA classified according to the following criteria:
? Age greater than or equal to 50 years
? History of ESR (greater than 50 mm/hour)
? AND at least one of the following:
? Unequivocal cranial symptoms of GCA (new onset localized headache, scalp or temporal artery tenderness, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain upon mastication)
? Symptoms of polymyalgia rheumatica (PMR), defined as shoulder and/or hip girdle pain associated with inflammatory morning stiffness
? AND at least one of the following:
? Temporal artery biopsy revealing features of GCA
? Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as magnetic resonance angiography (MRA), computed tomography angiography (CTA), or positron emission tomography computed tomography angiography (PET-CTA)
New-onset or refractory active disease defined as follows:
? New onset: diagnosis of GCA within 6 weeks of baseline visit
? Refractory: diagnosis of GCA >6 weeks before baseline visit and previous treatment with ?40 mg/day prednisone (or equivalent) for at least 2 consecutive weeks at any time
AND
Active GCA within 6 weeks of baseline visit (active disease defined as the presence of clinical signs and symptoms [cranial or PMR] and ESR greater than or equal to 30 mm/hour or CRP greater than or equal to 1 mg/dL) |
Diagnóstico de ACG: Edad ? 50 años. Antecedentes de VSG ? 50 mm/hora. Y al menos uno de los siguientes: Síntomas craneales inequívocos de ACG (cefalea localizada de nueva aparición, sensibilidad dolorosa o pulsación reducida de la arteria temporal, del cuero cabelludo, pérdida de visión debida a isquemia o dolor inexplicado de boca o mandíbula al masticar)
Síntomas de PMR, definida como dolor de hombros o cadera acompañado de rigidez matutina inflamatoria. Y al menos unode:Biopsia de arteria temporal que muestra características de ACG.Signos de vasculitis de los grandes vasos mediante angiografía o pruebas de imágenes transversales como la ARM, la ATC o ATC-TEP
Patología activa de nueva aparición o resistente al tratamiento definida como:
Nueva: diagnóstico de ACG en las 6 sem previas a la visita basal Resistente: diagnóstico de ACG > 6 sem antes de la visita basal y tratamiento previo en cualquier momento con ? 40 mg/día de prednisona (o equi) durante al menos 2 sem consecutivas. ACG act las 6 sem previas a la visita basal (patología activa def como la presencia de signos y síntomas [craneales o PMR] y una VSG ? 30 mm/hora o una PCR ? 1 mg/dl) |
|
| E.4 | Principal exclusion criteria |
- Recent or incoming major surgery
- Organ transplantation recipient (except corneas within 3 months prior to baseline visit)
- Major ischemic event, unrelated to giant cell arteritis, within 12 weeks of screening
- Prior treatment with any of the following:
- Investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening visit
- Cell-depleting agents (e.g. anti CD 20)
- Tocilizumab
- Tofacitinib
- Alkylating agents including CYC within 6
months of baseline
- HCQ, CsA, AZA, or MMF within 4 weeks
of baseline
- Tumor necrosis factor inhibitors within 2-8 weeks of baseline
- Anakinra within 1 week of baseline
- Corticosteroids for conditions other than
GCA
- IV corticosteroids within 6 weeks of
baseline
- History of severe allergic reactions to
monoclonal antibodies
- Evidence of serious uncontrolled
concomitant disease (e.g. cardiovascular,
respiratory, renal, endocrine)
- Current liver disease that could interfere
with the trial as determined by the
investigator
- History of diverticulitis, inflammatory bowel disease, or other symptomatic GI tract condition that might predispose to bowel perforation
- Infections:
- Active current or history of recurrent
bacterial, viral fungal, mycobacterial, or
other infection |
Cirugía mayor o cirugía mayor programada Órganos trasplantados (a excepción del trasplante de córnea realizado más de 3 meses antes de la selección)
Episodio isquémico mayor, no relacionado con la ACG, en las 12 sem previas a la selección
Exclusiones relacionadas con los tratamientos previos o concomitantes
Tratamiento con cualquier fármaco en investigación en las 12 sem (o 5 semividas del fármaco en investigación, lo que suponga más tiempo) previas a la selección.
Tratamiento previo con citorreductores, ej anti-CD20. Tocilizumab, Tofacitinib
Tratamiento con gammaglobulina IV o plasmaféresis en los 6 meses previos a la visita basal
Tratamiento previo con alquilantes, como el clorambucilo, o con irradiación linfática total.
Inmunización con una vacuna de organismos vivos o atenuados en las 4 semanas previas a la visita basal.
Tratamiento con hidroxicloroquina, ciclosporina A, azatioprina o MMF en las 4 semanas previas a la visita basal.
Tratamiento con etanercept en las 2 sem previas; con infliximab, certolizumab, golimumab, abatacept o adalimumab en las 8 sem previas; o con anakinra en la semana previa a la visita basal.
Tratamiento previo con tofacitinib.
Tratamiento con ciclofosfamida en los 6 meses previos a la visita basal.
Los pacientes que necesiten corticoides sistémicos para otras enfermedades distintas de la ACG que, en opinión del investigador, puedan interferir con la observancia de la pauta descendente de prednisona o con la evaluación de la eficacia en respuesta al producto ensayado.
Utilización crónica de corticoides sistémicos durante > 4 años o imposibilidad de retirar, en opinión del investigador, el tratamiento con corticoides mediante la pauta descendente definida por el protocolo por existir pruebas o sospecha de insuficiencia suprarrenal.
Administración de > 100 mg diarios de metilprednisolona intravenosa en las 6 semanas anteriores a la visita basal.
Antecedentes de reacciones alérgicas graves o anafilácticas a los anticuerpos monoclonales humanos, humanizados o múridos, o a la prednisona.
Signos de patología concomitante grave e incontrolada de carácter cardiovascular, nervioso, pulmonar (incluida la neumopatía obstructiva), renal, hepático, endocrino (incluida la diabetes mellitus no controlada), psiquiátrico, osteoporótico//osteomalácico, glaucomatoso, corneal (úlceras o lesiones) o gastrointestinal.
Hepatopatía actual determinada por el investigador.
Antecedentes de diverticulitis, diverticulosis con necesidad de tratamiento antibiótico o enteropatía ulcerativa crónica como la enfermedad de Crohn y la colitis ulcerosa, u otras afecciones intestinales que pudieran predisponer al paciente a presentar perforaciones.
Presencia activa o antecedentes de infecciones recurrentes bacterianas, víricas, micóticas, micobacterianas o de otro tipo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of patients in sustained remission at Week 52 |
| Proporción de pacientes en remisión en la semana 52 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- The proportion of patients in sustained remission at Week 52 in the TCZ treatment groups versus the placebo group with 52-week prednisone taper
- Time to first GCA disease flare after clinical remission (up to 52 weeks)
- Summary of total cumulative prednisone dose over 52 weeks
- Change from baseline in SF-36 (Physical and Mental Component Summaries) at 52 weeks
- Change from baseline in PGA of disease activity (VAS scale) at 52 weeks |
-La proporción de pacientes en remisión sostenida en la semana 52 en los grupos de tratamiento con TCZ versus el grupo placebo con 52 semanas de prednisona disminuida de forma gradual
-Tiempo de la primera señal de enfermedad de GCA después de la remisión clínica (hasta 52 semanas)
-Resumen de la dosis total acumulativa de prednisona durante 52 semanas
-Cambiar de línea de base en el SF-36 (física y Mental de componente de resúmenes) en 52 semanas
-Cambio desde el inicio en PGA de la actividad de la enfermedad (escala VAS) en 52 semanas |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of Life |
| Calidad de vida |
|
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| 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 |
| Canada |
| Denmark |
| France |
| Italy |
| Austria |
| Netherlands |
| Norway |
| Portugal |
| Sweden |
| Germany |
| Spain |
| Poland |
| 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
|
| The end of the study is defined as the date when the last participating patient completes the last scheduled visit or when the Sponsor decides to discontinue the study or development program |
| El fin del estudio se define como la fecha cuando el último paciente participante completa la última visita establecida o cuando el promotor decide interrumpir el estudio o desarrollo del programa |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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