| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis |
| Artritis Reumatoide |
|
| E.1.1.1 | Medical condition in easily understood language |
| An inflammatory arthritis that affects joints |
| Inflamación artrítica que afecta a las articulaciones |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| 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 |
| The primary objective of this endpoint study is to evaluate the safety of tofacitinib at two doses versus TNFi; the co-primary endpoints are adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies excluding non-melanoma skin cancers during study participation. |
| El objetivo primario de este estudio es evaluar la seguridad de tofacitinib a dos dosis en comparación con un TNFi; los criterios de valoración co-principales son los acontecimientos adversos cardiovasculares graves adjudicados (major adverse cardiovascular events, MACE) y las neoplasias malignas adjudicadas excepto el cáncer de piel no melanoma durante la participación en el estudio |
|
| E.2.2 | Secondary objectives of the trial |
| Not Applicable |
| No aplicable |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
2.Must be at least 50 years of age or older.
3.Has moderate to severe rheumatoid arthritis inadequately controlled with methotrexate alone with a score of 6 or greater on the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis
4.Has ?6 tender/painful joints on motion and ?6 swollen joints (28 joint count)
5.Has a C-reactive protein measured by a high sensitivity assay (hs-CRP) ?0.3 mg/dL in the central laboratory
6.Meets Class I, II or III of the American College of Rheumatology (ACR) 1991 Revised Criteria for Global Functional Status in RA where usual self-care activities including dressing, feeding, bathing, grooming, and toileting; avocational (recreational and/or leisure) and vocational (work, school, homemaking) activities are subject-desired and age and sex-specific.
7.Has taken methotrexate continuously for at least 4 months prior to the Screening visit and has taken a stable weekly dose of methotrexate with supplemental folic or folinic acid for at least 6 weeks prior to the Baseline visit.
?Methotrexate doses less than 15 mg/week are allowed only in the presence of documented intolerance or toxicity from higher doses
?Doses higher than 25 mg/week are not permitted under any circumstances
?Folic acid doses should be at least 5 mg per week; folinic acid doses should be at least 2.5 mg per week.
8.Have at least one of the following cardiovascular risk factors at screening:
?Current cigarette smoker
?Diagnosis of hypertension
?High density lipoprotein (HDL) <40 mg/dL
?Diabetes mellitus
?Family history of premature coronary heart disease
?Presence of extra-articular disease associated with rheumatoid arthritis, which may include nodules, Sjögren?s syndrome, anemia of chronic disease and pulmonary manifestations
?History of coronary artery disease including a history of revascularization procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome
9.Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
10.Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment.
11.Female subjects of childbearing potential must test negative for pregnancy.
12.Female subjects who are not of childbearing potential must meet at least one of the following criteria:
?Have undergone a documented hysterectomy and/or bilateral oophorectomy
?Have medically confirmed ovarian failure or
?Achieved post menopausal status
13.Subjects must screen negative for active tuberculosis or inadequately treated tuberculosis infection (active or latent) as evidenced by the following:
a.Negative QuantiFERON Gold®? In-Tube test performed at screening
?This is required unless the subject has been adequately treated for active or latent tuberculosis or a negative QuantiFERON Gold®? In-Tube test was previously performed and documented within the 3 months prior to screening.
?A negative tuberculin skin test (TST) is one that is <5 mm induration and it can be substituted for the QuantiFERON Gold®? In-Tube test only if the central laboratory is unable to perform the test or the test is reported as indeterminate after at least 2 successive attempts.
?It is strongly recommended that subjects with a history of Bacille Calmette Guérin (BCG) vaccination be tested with the QuantiFERON Gold®? In-Tube test.
b.Chest radiograph taken at screening without changes suggestive of active tuberculosis (TB) infection, unless previously performed and documented within 3 months prior to screening
c.No history of tuberculosis infection unless one of the following is documented:
?Subject with prior or current latent tuberculosis has no evidence of active tuberculosis and must be taking or have completed an adequate course of therapy for latent tuberculosis (9 months of isoniazid in a locale where rates of primary multi-drug resistant TB infection are <5% or an alternative regimen recognized by the World Health Organization) and a chest radiograph is negative for active disease; the chest radiograph must be obtained at screening or, if previously performed and documented, within 3 months prior to screening.
?Subject with prior active tuberculosis has no current evidence of active disease and has completed an adequate course of therapy for active tuberculosis (a multi-drug regimen recognized by the World Health Organization) and a chest radiograph is negative for active disease; the chest radiograph must be obtained at screening or, if previously performed and documented, within 3 months prior to screening |
1. Prueba de un documento de consentimiento informado, firmado y fechado personalmente- 2. Debe tener al menos 50 años de edad o más.
3. Tiene artritis reumatoide moderada a grave, mal controlada con metotrexato solo, con una puntuación de 6 o mayor en los criterios de clasificación de 2010 del Colegio Americano de Reumatología/Liga Europea contra el Reumatismo para la artritis reumatoide. 4. Tiene ?6 articulaciones sensibles/dolorosas en movimiento y ?6 articulaciones inflamadas (recuento de 28 articulaciones).
5. Tiene una proteína C reactiva medida mediante un análisis de alta sensibilidad (PCRas) ?0,3 mg/dl en el laboratorio central.
6. Cumple con la clase I, II o III según los criterios revisados de 1991 del American College of Rheumatology (ACR) para el estado funcional global en AR, donde las actividades habituales de cuidado personal
? Clase I - Capacidad completa para realizar las actividades habituales de la vida diaria.? Clase II - Capacidad para realizar todas las actividades habituales de cuidado personal y laborales, pero con limitación en las actividades lúdicas.
? Clase III - Capacidad para realizar todas las actividades habituales de cuidado personal, pero con limitación en las actividades. 7. Ha tomado metotrexato de manera continua durante al menos 4 meses antes de la visita de selección y ha tomado una dosis estable semanal de metotrexato con un suplemento de ácido fólico o ácido folínico durante al menos 6 semanas antes de la visita basal.
? Las dosis de metotrexato menores de 15 mg/semana están permitidas únicamente en presencia de una intolerancia o toxicidad documentadas debidas a dosis elevadas.
? Las dosis mayores de 25 mg/semana no están permitidas en ningún caso.
? Las dosis de ácido fólico deben ser al menos de 5 mg por semana; las dosis de ácido folínico deben ser al menos de 2,5 mg por semana.
8. Presentan al menos uno de los siguientes factores de riesgo cardiovascular en la selección:
? Fumador de cigarrillos en la actualidad.
? Diagnóstico de hipertensión.
? Lipoproteínas de alta densidad (HDL) < 40 mg/dl.
? Diabetes mellitus.
? Antecedentes familiares de cardiopatía coronaria (CC); ? Presencia de enfermedad extra-articular asociada con artritis reumatoide, que podría incluir nódulos, síndrome de Sjögren, anemia de la enfermedad crónica y manifestaciones pulmonares.
? Historial de enfermedad arterial coronaria- 9. Los pacientes deben estar dispuestos y ser capaces de cumplir con las visitas programadas, el plan de tratamiento, las pruebas en laboratorio y otros procedimientos del estudio.
10. Los pacientes de sexo masculino y femenino con capacidad de procrear deben acceder a utilizar un método anticonceptivo de eficacia elevada durante todo el estudio y durante al menos los 28 días siguientes a la administración de la última dosis del tratamiento asignado.
11. Las pacientes con capacidad de procrear deben presentar una prueba negativa de embarazo.
12. Las pacientes sin capacidad de procrear deben cumplir al menos uno de los siguientes criterios: histerectomía y/o a una ooforectomía bilateral documentadas;
? se les ha confirmado médicamente insuficiencia ovárica; o ? están en la postmenopausia
13. Los pacientes deben presentar un resultado negativo para la tuberculosis activa o para la infección de tuberculosis (activa o latente) tratada de manera inadecuada según lo demuestra lo siguiente:
a. Resultado negativo para la prueba QuantiFERON Gold®TM en tubo realizada en la selección.
? Esto es obligatorio a menos que el paciente haya sido tratado de manera adecuada para tuberculosis activa o latente o que presente un resultado negativo en la prueba QuantiFERON Gold®TM en tubo realizada previamente y documentada en los 3 meses anteriores a la selección.
? Una prueba cutánea de la tuberculina (PCT) negativa es aquella con una induración < 5 mm y puede reemplazar a la prueba QuantiFERON Gold®TM en tubo.
? Se recomienda que los pacientes con un historial de vacunación contra el bacilo Calmette-Guérin (BCG) sean analizados con la prueba QuantiFERON Gold®TM .
b. Radiografía de tórax realizada en la selección sin cambios que indiquen una infección de tuberculosis (TB) activa. c. Sin antecedentes de infección de tuberculosis a menos que se documente uno de los siguientes:
Paciente con tuberculosis latente previa o actual no presenta indicios de tuberculosis activa y debe estar tomando o haber finalizado un ciclo de terapia adecuado para la tuberculosis latente (9 meses de isoniacida en un lugar donde las tasas de infección por TB con resistencia primaria a múltiples fármacos sea < 5 % o una terapia alternativa reconocida por la Organización Mundial de la Salud) y tiene una radiografía de tórax negativa para la enfermedad activa; la radiografía de tórax debe obtenerse en la selección o, si se ha realizado y documentado previamente, debe haberse hecho en los 3 meses anteriores a la selección |
|
| E.4 | Principal exclusion criteria |
1.Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
2.Subjects who are classified Class IV of the ACR 1991 Revised Criteria for Global Functional Status in RA (ie, are limited in their ability to perform usual self-care, vocational, and avocational activities).
3.Pregnant females; breastfeeding females; sexually active males and females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after last dose of investigational product.
4.Subjects with infections or history of infections:
a.Any infection requiring treatment within 2 weeks prior to the Baseline visit.
b.Any infection requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator, within the past 6 months.
c.Infected joint prosthesis at any time with the prosthesis still in situ.
d.Recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
e.Subjects will be screened for human immunodeficiency virus (HIV). Subjects who test positive for HIV will be excluded from the study.
f.Subjects will be screened for hepatitis B virus infection. Subjects with hepatitis B surface antigen (HBsAg) negative testing but who test positive for hepatitis B core antibody (HBcAb) must have further testing for hepatitis B surface antibody (HBsAb). If HBsAb is negative, the subject will be excluded from the study.
g.Subjects will be screened for hepatitis C virus antibodies (HCV Ab). Subjects with positive HCV Ab tests will be reflex tested for hepatitis C virus ribonucleic acid (HCV RNA). Only subjects with negative HCV Ab or HCV RNA will be allowed to enroll in the study.
h.Subjects are excluded for current active tuberculosis infection or prior active or latent tuberculosis that was inadequately treated or cannot be documented (See Section 4.1 Inclusion Criteria #13).
5.Subjects with any current malignancy or a history of malignancy, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
6.Subjects with any uncontrolled clinically significant laboratory abnormality or any of the following laboratory abnormalities:
a.Evidence of hematopoietic disorder or hemoglobin <9 g/dL
b.White blood cell count <3.0 x 109/L (<3000/mm3)
c.Absolute lymphocyte count <0.5 x 109/L (<500/mm3)
d.Absolute neutrophil count <1.0 x 109/L (<1000/mm3)
e.Platelet count <100 x 109/L (<100,000/mm3)
f.Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >1.5 times the upper limit of normal (x ULN)
g.Estimated glomerular filtration rate (GFR) <60 mL/min using the Cockcroft-Gault formula (Appendix 3).
7.Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks or 5 half-lives (whichever is longer) after discontinuation of the investigational compound before the current study begins and/or during study participation, unless further restrictions to class of compound are specified in Section 4.2 Exclusion Criteria and Section 5.5 Concomitant Medication(s).
8.Subjects requiring or have received any prohibited concomitant medication as outlined in Appendix 2, including:
a.Subjects who have received live or live attenuated vaccines within 6 weeks prior to the first dose of study drug or at any time during treatment or within 6 weeks following discontinuation of study drug (See Section 4.4.2).
b.Subjects who have been previously treated with tofacitinib.
c.Subjects who are being treated with biologic or non-biologic DMARDs other than MTX or antimalarials within their specified washout window at study entry (see Table 1).
d.Subjects who previously experienced inadequate response, intolerance, allergy or hypersensitivity to adalimumab (US, Puerto Rico and Canada) or to etanercept (all other countries) or for whom adalimumab (US, Puerto Rico and Canada) or etanercept (all other countries) are contraindicated.
e.Subjects who are being treated with corticosteroids, other than low dose oral corticosteroids in doses equivalent to ?10 mg prednisone per day at study entry.
f.Subjects who require concomitant treatment with medications that are potent inhibitors of cytochrome P450 3A4 (CYP3A4), both moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19, or potent CYP inducers.
9.Subjects who have Class III or Class IV heart failure according to the New York Heart Association (NYHA) functional classification system.
See protocol for Exclusion criteria 10-16 |
1. Pacientes que sean miembros del personal del centro de investigación directamente implicados en la realización del ensayo, así como sus familiares, miembros del personal del centro.
2. Pacientes que se clasifican en la clase IV según los criterios revisados de 1991 de la ACR para el estado funcional global en AR (es decir, limitación en la capacidad para realizar las actividades habituales de cuidado personal, laborales y lúdicas).
3. Mujeres embarazadas; mujeres en período de lactancia; hombres y mujeres sexualmente activos y con capacidad de procrear que no desean o no pueden usar un método anticonceptivo de elevada eficacia tal como se describe en el protocolo durante todo el estudio y durante al menos 28 días después de la última dosis del producto en investigación.
4. Pacientes con infecciones o antecedentes de infecciones:
a. Cualquier infección que requiera tratamiento en las 2 semanas previas a la visita basal.
b. Cualquier infección que requiera hospitalización, antibióticos parenterales, o que el investigador considere clínicamente significativa, en los 6 meses anteriores.
c. Prótesis articular infectada en cualquier momento, con la prótesis todavía colocada.
d. Herpes zóster recurrente (más de un episodio) o diseminado (un único episodio), o herpes simple diseminado (un único episodio).
e. Se harán pruebas de cribado en los pacientes para el virus de la inmunodeficiencia humana (VIH). Los pacientes con un resultado positivo para el VIH se excluirán del estudio.
f. Se harán pruebas de cribado en los pacientes para la infección por el virus de la hepatitis B. Los pacientes con un resultado negativo para el antígeno de superficie de la hepatitis B (HBsAg) pero positivo para los anticuerpos contra el antígeno central de la hepatitis B (anti-HBc) deben someterse a un análisis adicional para los anticuerpos contra el antígeno de superficie de la hepatitis B (anti-HBs). g. Se harán pruebas de cribado en los pacientes para los anticuerpos contra el virus de la hepatitis C (anti-VHC). h. Los pacientes están excluidos por infección actual de tuberculosis activa o infección previa de tuberculosis activa o latente que fue tratada de una manera inadecuada o no puede. 5. Los pacientes con presencia o antecedentes de neoplasia maligna, a excepción del carcinoma basocelular o el carcinoma espinocelular de la piel, o el carcinoma cervical in situ, no metastásicos y debidamente tratados o extirpados.
6. Los pacientes con cualquier anomalía de laboratorio clínicamente relevante y no controlada o cualquiera de las siguientes anomalías de laboratorio:
a. Evidencias de trastornos hematopoyéticos o niveles de hemoglobina < 9 g/dl.
b. Recuento de leucocitos < 3,0 x 109/l (< 3000/mm3).
c. Recuento absoluto de linfocitos < 0,5 x 109/l (< 500/mm3).
d. Recuento absoluto de neutrófilos < 1,0 x 109/l (< 1000/mm3).
e. Recuento de plaquetas < 100 x 109/l (< 100 000/mm3).
f. Alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST) > 1,5 veces el límite superior de la normalidad (x LSN).
g. Tasa de filtración glomerular (TFG) calculada < 60 ml/min usando la fórmula de Cockcroft-Gault (Appendix 3).
7. Participación en otros estudios que incluyan fármaco(s) de investigación (fases I-IV) en las 4 semanas o 5 semividas (lo que sea más largo) tras la interrupción del compuesto en investigación antes de que empiece el presente estudio y/o durante la participación en el mismo, a menos que se especifiquen más restricciones en el tipo de compuesto 8. Pacientes que requieren o han recibido cualquiera de las medicaciones concomitantes prohibidas, incluidos:
a. Pacientes que han recibidos vacunas vivas o vivas atenuadas en las 6 semanas previas a la primera dosis del fármaco del estudio o en cualquier momento durante el tratamiento, o en las 6 semanas posteriores a la interrupción del fármaco del estudio.
b. Pacientes que han sido tratados previamente con tofacitinib.
c. Pacientes que están siendo tratados con FARME biológicos o no biológicos, distintos al MTX o a medicamentos contra la malaria.d. Pacientes que han experimentado previamente una respuesta inadecuada, intolerancia, alergia o hipersensibilidad a adalimumab (EE. UU., Puerto Rico o Canadá) o etanercept (los demás países), o para los cuales está contraindicado adalimumab o etanercept.
e. Pacientes que están siendo tratados con corticosteroides, que no sean dosis bajas por vía oral de corticosteroides a una dosis equivalente a ? 10 mg de prednisona al día en el momento de entrada en el estudio.
f. Pacientes que requieren un tratamiento concomitante con medicamentos que son inhibidores potentes del citocromo P450 3A4 (CYP3A4), inhibidores moderados de CYP3A4 e inhibidores potentes de CYP2C19, o los inductores potentes del CYP.
9. Pacientes que presentan una insuficiencia cardiaca de clase III o clase IV según el sistema de clasificación funcional de la Asociación del Corazón de Nueva York. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Endpoints
The safety endpoints will be collected and analyzed for all subjects in the study, through the end of the study.
Co-Primary Safety Endpoints
The following co-primary safety endpoints will be analyzed to provide comparative rates for tofacitinib vs. the combined TNFi:
?Malignancies, excluding non-melanoma skin cancers (adjudicated)
?Major adverse cardiovascular events (adjudicated) defined as cardiovascular death including deaths due to coronary, cerebrovascular, cardiac (eg, sudden cardiac death) events and non-cardiac vascular deaths (eg, pulmonary embolism), and non-fatal cardiovascular events including myocardial infarction and cerebrovascular events. |
Criterios de Seguridad
Se recopilarán y analizarán los criterios de valoración de la seguridad para todos los pacientes del estudio, hasta el final del estudio.
Criterios de seguridad co-primarios
Se analizarán los siguientes criterios de valoración de la seguridad co-principales con el fin de proporcionar tasas comparativas para tofacitinib en comparación con los TNFi combinados:
? Neoplasias malignas, excluido el cáncer de piel no melanoma (adjudicadas).
? Acontecimientos adversos cardiovasculares graves (MACE) (adjudicados). Muerte cardiovascular.
? Muerte debida a infarto agudo de miocardio (IAM).
? Muerte súbita cardiaca.
? Muerte debida a insuficiencia cardiaca.
? Muerte debida a accidente cerebrovascular.
? Muerte debida a procedimientos cardiovasculares.
? Muerte debida a hemorragia cardiovascular.
? Muerte debida a otras causas cardiovasculares: enfermedad arterial periférica.
? Infarto de miocardio (IM) no mortal.
? Accidente cerebrovascular no mortal de cualquier tipo, incluidos los defectos neurológicos focales reversibles con indicios en imagen |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Visit 1 [Day 1]
Visit 2 [Month 2]
Visit 3 [Month 3]
Visit 4 [Month 6]
Visits 5, 9, 13, 17, 21 [Months 9, 21, 33,45, 57]
Visit 6, 10, 14, 18, 22 [Months 12, 24, 36, 48, 60]
Visits 7, 11, 15, 19 [Months 15, 27, 39, 51]
Visits 8, 12, 16, 20 [Months 18, 30, 42, 54]
End of Study Visit [Month 60] |
Visita 1 (Día 1)
Visita 2 (Mes 2)
Visita 3 (Mes 3)
Visita 4 (Mes 6)
Visitas 5, 9, 13, 17, 21 [Meses 9, 21, 33,45, 57]
Visitas 6, 10, 14, 18, 22 [Meses 12, 24, 36, 48, 60]
Visitas 7, 11, 15, 19 [Meses 15, 27, 39, 51]
Visitas 8, 12, 16, 20 [Meses 18, 30, 42, 54]
Visita de fin de estudio [Mes 60] |
|
| E.5.2 | Secondary end point(s) |
Secondary Safety Endpoints
The secondary safety endpoints will include an evaluation of the following events:
?Opportunistic infection events including tuberculosis (adjudicated)
?Hepatic events (adjudicated)
?Cardiovascular events other than MACE (adjudicated)
?All adverse events (AEs), including serious adverse events (SAEs)
?Clinically significant abnormal laboratory parameters
?All cause mortality (adjudicated)
?Reasons for permanent or temporary discontinuation of study medication
Efficacy endpoints will include:
? Change from baseline to each post-baseline scheduled visit in DAS28-4 (CRP).
? Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI).
? Rate of remission at each post-baseline scheduled visit including:
? ACR-EULAR Boolean remission (defined as the subject satisfying all of the
following: tender joint count ? 1, swollen joint count ?1, C-reactive protein ?1 mg/dL, patient global assessment ?1 on a 0-10 scale)
? SDAI ? 3.3
?CDAI ?2.8
? Rate of low disease activity (LDA) at each post-baseline scheduled visit including:
? SDAI ? 11
? CDAI ?10
? DAS28-4(CRP) ?3.2
? ACR20, ACR50, and ACR70 response rate of at each post-baseline scheduled visit
? Change from baseline to each post-baseline scheduled visit in the HAQ-DI |
Los criterios de valoración secundarios de la seguridad incluirán una evaluación de los siguientes acontecimientos:
? Acontecimientos de infección oportunista incluida la tuberculosis (adjudicados).
? Acontecimientos hepáticos (adjudicados).
? Acontecimientos cardiovasculares distintos a MACE (adjudicados).
? Todos los acontecimientos adversos (AA), incluidos los acontecimientos adversos graves (AAG).
? Anomalías en los parámetros de laboratorio de relevancia clínica.
? Mortalidad general (adjudicada).
? Motivos para la interrupción permanente o temporal de la medicación del estudio. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Visit 1 [Day 1]
Visit 2 [Month 2]
Visit 3 [Month 3]
Visit 4 [Month 6]
Visits 5, 9, 13, 17, 21 [Months 9, 21, 33,45, 57]
Visit 6, 10, 14, 18, 22 [Months 12, 24, 36, 48, 60]
Visits 7, 11, 15, 19 [Months 15, 27, 39, 51]
Visits 8, 12, 16, 20 [Months 18, 30, 42, 54]
End of Study Visit [Month 60] |
Visita 3 [Mes 3]
Visita 4 [Mes 6]
Visitas 5, 9, 13, 17, 21 [Meses 9, 21, 33,45, 57]
Visitas 6, 10, 14, 18, 22 [Meses 12, 24, 36, 48, 60]
Visitas 7, 11, 15, 19 [Meses 15, 27, 39, 51]
Visitas 8, 12, 16, 20 [Meses 18, 30, 42, 54]
Visita fin de estudio [Mes 60] |
|
| 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 | Yes |
| 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) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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 | No |
| 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 | 3 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 110 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Chile |
| Colombia |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Sweden |
| Taiwan |
| Turkey |
| Ukraine |
| 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
|
| LVLS |
| Última visita de último paciente (UVUP) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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