| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ovarian neoplasms |
| Neoplasias ováricas |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ovarian cancer |
| Cáncer de ovarios |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051938 |
| E.1.2 | Term | Ovarian adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 the study is to evaluate the efficacy and safety of 5 different treatments involving atezolizumab, bevacizumab and/or acetylsalicylic acid in advanced recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer patients in order to select the optimal treatments for further development in phase III. |
| El objetivo principal del estudio consiste en evaluar la eficacia y la seguridad de 5 tratamientos distintos compuestos por atezolizumab, bevacizumab y/o ácido acetilsalicílico/placebo en pacientes con cáncer de ovario, de trompa de Falopio o peritoneal primario, recidivante y resistente al platino, con el fin de seleccionar los tratamientos óptimos para su futuro desarrollo en la fase III. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to:
♦assess the biological activity and immunological effects of each treatment in the tumor microenvironment and in the peripheral blood
♦assess the effect of treatment on disease control and overall survival |
Los objetivos secundarios del estudio consisten en:
♦ Evaluar la actividad biológica y los efectos inmunológicos de cada tratamiento en el microambiente tumoral y en la sangre periférica
♦ Evaluar el efecto del tratamiento sobre el control de la enfermedad y la supervivencia global |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
♦Recurrent, histologically proven, platinum-resistant, epithelial ovarian cancer, fallopian tube and primary peritoneal cancer in advanced or metastatic stage. Histological diagnosis by image guided biopsy, laparoscopy or laparotomy. Tumors diagnosed on cytology only and borderline tumors (i.e. low malignant potential) are excluded
♦At least one lesion accessible to biopsy without putting patient at risk
♦Prior systemic (chemotherapy, hormonal therapy, biologic agents, and/or vaccines) or radiation treatment:
*Systemic anti-tumoral treatment: wash-out period of 21 days prior to the first study treatment
*Any number of platinum-based chemotherapy lines are allowed but a maximum of 2 previous non-platinum containing lines
*Prior treatment with bevacizumab or other targeted agents against VEGF or VEGF receptor is allowed, but at least 18 weeks must have elapsed since their last administration
*Eligible patients with ≤ 2 previous treatment lines must have been previously exposed to bevacizumab or other targeted agents against VEGF or VEGF receptor
*Recovery from any toxic effects of prior therapy to ≤ Grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0) except fatigue or alopecia.
*Radiation therapy: recovery period of 14 days prior to the first study treatment; exception: single fraction radiotherapy with the indication of pain control and no prior radiation to the pelvis
♦Age ≥18 years
♦WHO PS: 0-2 for patients having received no more than two previous lines of therapy. WHO PS: 0-1 for patients having received >2 previous lines of therapy
♦Life expectancy of ≥ 12 weeks
♦Adequate hematologic and end organ function, defined by laboratory results (see protocol at section 3.1 for details) obtained within 14 days prior to randomization
♦Patients with past/resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. HBV DNA must be obtained in patients with positive hepatitis B core antibody prior to randomization
♦Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA
♦Women of childbearing potential (WOCP: defined as a sexually mature woman who 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally post-menopausal (amenorrhoea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)) must:
Have a negative serum pregnancy test within 7 days prior to randomization.
Agree to remain sexually abstinent, have a partner who is sterile (i.e., vasectomy), or use two medically effective methods of contraception during dosing and through 6 months after last study treatment. An effective method is the combination of the following (a+b): a. Hormonal method eg, birth control pills; b. Placement of an intrauterine device (IUD) or intrauterine system (fUS), barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/ gel/film/ cream/vaginal suppository. This requirement should be followed from screening through 24 weeks after last study treatment.
During treatment: Patient should agree to urine pregnancy test to be performed before each treatment;
Agree to discontinue treatment in case of pregnancy or positive pregnancy test.
♦Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations |
Cáncer ovárico epitelial, de trompa de Falopio o peritoneal primario, recidivante, confirmado histológicamente y resistente al platino, en estado avanzado o metastásico. Diagnóstico histológico realizado mediante biopsia guiada por imagen, laparoscopia o laparotomía. Quedan excluidos los tumores cuyo diagnóstico solo se ha realizado mediante citología, así como los tumores “borderline” o de bajo potencial maligno.
♦ Será preciso disponer como mínimo de una lesión accesible para la biopsia sin poner a la paciente en riesgo.
♦ Edad ≥ 18 años
♦ Estado funcional (EF) de la OMS: 0-2 en las pacientes que hayan recibido como máximo dos líneas de tratamiento anteriores. EF de la OMS: 0-1 en las pacientes que hayan recibido más de dos líneas de tratamiento anteriores.
♦ Esperanza de vida ≥ 12 semanas
♦ Adecuadas funciones hematológicas y orgánicas
♦ Quimioterapia anterior o bevacizumab:
♦ Se permiten cualquier número de líneas previas de quimioterapia basada en platino, pero sólo un máximo de dos líneas previas con agentes no-platino.
♦ Los tratamientos previos con bevacizumab u otros agentes dirigidos contra el VEGF o su receptor VEGFR están permitidos, pero deben haber transcurridos 18 semanas desde su última administración
♦ Las enfermas elegibles que hayan recibido igual o menos de 2 líneas previas de tratamiento deben haber sido previamente expuestas a bevacizumab u otros agentes dirigidos contra VEGF o su receptor VEGFR
♦ Las pacientes pueden haber recibido tratamientos anteriores siempre que se cumplan las condiciones siguientes:
♦ Radioterapia: período de lavado farmacológico de 14 días antes del primer tratamiento del estudio, a excepción de la radioterapia en fracción única con la indicación de analgesia
♦ Tratamiento sistémico antitumoral: período de lavado farmacológico de 21 días antes del primer tratamiento del estudio
♦ Recuperación de todos los efectos tóxicos del tratamiento anterior hasta el grado ≤ 1 según los criterios comunes de terminología para acontecimientos adversos del Instituto Nacional del Cáncer de los EE. UU. (NCI CTCAE v 4.0), salvo el cansancio o la alopecia.
Formulario de consentimiento informado firmado |
|
| E.4 | Principal exclusion criteria |
-current, recent (within 4 weeks of randomization}, or planned
participation in an experimental drug study
-uncontrolled hypercalcemia [>1.5 mmoi/L (4.8 mg/dl) ionized
calcium, or Total Ca>3 mmoi/L (12 mg/dl) or corrected serum calcium
>ULN] or symptomatic hypercalcemia requiring continued use of
bisphosphonate therapy or denosumab
-symptomatic brain or leptomeningeal disease; any brain metastases
not stable for at least 6 months
-presence of uncontrolled pleural effusion, pericardial effusion, or
ascites requiring recurrent drainage procedures (once monthly or more frequently)
-significant cardiovascular disease, such as:
*inadequately controlled hypertension (defined as systolic blood
pressure>150 mm Hg and/or diastolic blood pressure>100 mm Hg
despite intensive medical management} or prior history of hypertensive crisis or hypertensive encephalopathy. Anti-hypertensive therapy is allowed.
*New York Heart Association Class II or greater congestive heart failure and history of myocardial infarction or unstable angina within 6 months prior to randomization (Appendix D)
*significant vascular disease including stroke, transient ischemic attack, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis within 6 months prior to randomization
-evidence of bleeding diathesis or significant coagulopathy (in the
absence of therapeutic anticoagulation) and current or recent (within 10 days prior to randomization} use of dipyridamole, ticlopidine,
clopidogrel, cilostazol, prasugrel, or ticagrelor; or use of full dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic} purpose
-obvious signs of, or risks for gastrointestinal fistula formation or
perforation, such as:
*History of abdominal or tracheoesophageal fistula or gastrointestinal
perforation within 6 months prior to randomization
*clinical signs or symptoms of gastrointestinal obstruction or
requirement for routine parenteral hydration, parenteral nutrition, or
tube feeding
-serious, non-healing or dehiscing wound, active ulcer, or untreated
bone fracture. Surgery (including open but not core biopsy} within 4
weeks prior to randomization, or anticipation of the need for major
surgery during study treatment
-proteinuria, as demonstrated by urine dipstick >1+ or> 1 .0 g of
protein in a 24-hour urine collection (All patients with > or = 2+ protein on dipstick urinalysis at baseline must undergo a 24 hour urine
collection for protein and will remain eligible if < 1.0 g of protein
detected} within 2 weeks of randomization
-history of inflammatory bowel disease or any autoimmune disease,
including but not limited to myasthenia gravis, myositis, autoimmune
hepatitis, systemic lupus erythematosus, rheumatoid arthritis, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis
-history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans}, drug-induced pneumonitis, idiopathic
pneumonitis, or evidence of active pneumonitis on screening chest CT
scan
-positivity for infections:
*signs or symptoms of infection or therapeutic use of antibiotics (except prophylactic antibiotics} within 2 weeks prior to randomization and severe infections within 4 weeks prior to randomization, including but
not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
*HIV (test to be performed within 14 days of randomization)
*active or chronic hepatitis B (defined as having a positive hepatitis B
surface antigen [HBsAg] test at screening), or hepatitis C
*active tuberculosis (all patients will have tuberculin skin test or IGRA
done locally prior to inclusion to study)
-conditions leading to immune suppression or stimulation of the
immune system
-malignancies other than ovarian cancer within 5 years prior to
randomization, with the exception of those with a negligible risk of
metastasis or death, treated with expected curative outcome (such as
adequately treated carcinoma in situ of the cervix, basal or squamous
cell skin cancer, ductal carcinoma in situ treated surgically with curative intent, and non-muscle invasive urothelial cell carcinoma)
-No use of acetylsalicylic acid, NSAIDs or other COX- 2 inhibitors that
cannot be stopped at baseline and for the whole duration of the study. Occasional use is allowed.
-breast feeding during dosing and through 6 months after last study
treatment |
-Participación en un estudio con un fármaco experimental en el momento de la entrada en el estudio, recientemente (en las 4 semanas de la randomización), o que se prevé que va a participar en otro estudio.
-Hipercalcemia no controlada (< 1.5 mmol/L) (4.8 mg/dl) de calcio ionizado, o un calcio total > 3 mmol/L (12 mg/dl) o calcio sérico corregido >ULN) o hipercalcemia sintomática que requiere el uso de terapia con bisfosfonatos, o denosumab
-Enfermedad cerebral o leptomeningea sintomática; Cualquier metástasis cerebral no estable por al menos 6 meses.
-Presencia de derrame pleural no controlado, derrame pericárdico, o ascitis que requiere procedimientos de drenaje recurrentes (una vez al mes o más frecuentemente).
-Enfermedad cardiovascular significativa, tales como:
Hipertensión no controlada adecuadamente (definida como presión sistólica > 150 mm Hg y /o presión diastólica > de 100 mm de HG a pesar de un tratamiento médico intensivo, o previa historia de crisis hipertensiva o encefalopatía hipertensiva. La terapia antihipertensiva se permite.
Clase II o mayor de fracaso congestivo cardíaco de la Asociación Cardiológica de Nueva York, e historia de infarto de miocardio o angina inestable en los últimos 6 meses previos a al randomización (apéndice D).
* Enfermedad vascular significativa, incluyendo accidente cerebrovascular, ataque isquémico transitorio, aneurisma aórtico que requiere reparación quirúrgica o trombosis reciente arterial periférica en los 6 meses previos a la randomización.
Evidencia de diátesis hemorrágica o coagulopatía significativa (en ausencia de anticoagulación terapéutica) y uso actual o reciente (en los 10 días previos a la randomización) de dipiridamol, ticlopidina, clopidogrel, cilostazol, prasugrel, o ticagrelor, o el uso de dosis completas orales o parenterales de anticoagulantes o agentes trombolíticos con intención terapéutica (en contraste con el profiláctico).
Obvios signos de, o riesgo de formación de fistula gastrointestinal o perforación, tales como:
Historia de fistula abdominal o traqueo-esofágica o perforación gastrointestinal en los seis mees previos a la randomización.
Síntomas o signos clínicos de obstrucción intestinal, o requerimiento para una hidratación parenteral, nutrición parenteral o un tubo de alimentación.
-Heridas serias, que no curan o dehiscencias, ulceras activas, o fracturas óseas no tratadas. Cirugía en las 4 semanas previas a la randomización, o anticipación de la necesidad de cirugía mayor durante el tratamiento del estudio.
-Proteinuria, demostrada por una tira de orina > 1 + o > 1.0 g de proteínas en orina de 24 horas (todas las pacientes con > o = 2+ de proteínas en las tiras de orina a la entrada en el estudio, tienen necesariamente que realizar un test de proteínas en orina de 24 horas y seguirán siendo elegibles si se detectan < 1.0 g de proteínas en las dos semanas previas a la randomización.
-Historia de enfermedad inflamatoria intestinal o de enfermedades autoinmunes, incluyendo, pero no sólo limitadas a miastenia gravis , miositis, hepatitis autoinmune, lupus eritematoso sistémico, artritis reumatoide, trombosis vascular asociada con síndrome antifosfolipídico, granulomatosis de Wegener, síndrome de SJögren, síndrome de Gullain-Barre, esclerosis múltiple, diabetes mellitus tipo I, vasculitis o glomerulonefritis.
-Historia de fibrosis pulmonar idiopática, neumonía organizada, neumonías inducidas por fármacos, neumonitis idiopática, o evidencia de neumonitis activa en la TAC torácica de cribado.
-Positividad por infecciones: Signos o síntomas de infección o uso terapéutico de antibióticos (excepto antibióticos profilácticos) en las dos semanas previas a la randomización e infecciones severas en las 4 semanas previas a la randomización, incluyendo, pero no sólo limitado a la hospitalización por complicaciones de infecciones, bacteriemia, o neumonía severa.
* HIV (un test diagnóstico debe realizarse en los 14 días de la randomización)
* Hepatitis B activa o crónica (definida como la presencia de un antígeno de la hepatitis B de superficie (HBsAg) en las pruebas de cribado), o hepatitis C
* Tuberculosis activa (todos los pacientes tendrán un test cutáneo de tuberculina o la realización de IGRA localmente, previo a la inclusión en el estudio.
-Condiciones que conducen a la inmunosupresión o estimulación del sistema immune.
_tumores malignos distintos a cáncer de ovario en los 5 años previos a la randomización, con la excepción de aaquellos con un riesgo despreciable de metástasis o muerte, tratados con expectativas de resultado de curación
-Ausencia de uso de ácido acetilsalicílico, antiinflamatorios no esteroideos (NSAIDs) o otros inhibidores de la COX-2 que no pueden ser discontinuados en el momento de la entrada en el estudio y por toda la duración del estudio. El uso ocasional esta permitido.
-Amamantar durante el tratamiento y durante 6 meses después del último tratamiento recibido del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is progression-free survival rate at 6 months (PFS-6) according to RECIST v1.1 as assessed by the local investigator. Safety is assessed according to CTCAE v4.0. |
Objetivo principal: tasa de supervivencia libre de progresión a los 6 meses (PFS-6) conforme a los criterios RECIST v 1.1 según la evaluación del investigador local.
Seguridad conforme a los CTCAE v 4.0. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| at 6 months |
| A los 6 meses |
|
| E.5.2 | Secondary end point(s) |
♦secondary endpoints are: overall survival, progression free survival, second progression free survival, clinical response, disease control and duration of response as measured by RECIST. Progression-free survival at 6 months, progression free survival, second progression-free survival and clinical response will also be assessed using irRECIST.
♦Tolerability will be summarized by the frequency of treatment regimen modification and reasons for stopping the treatment.
♦Tumor infiltrating lymphocytes (TIL) at enrolment will be analysed on tumor biopsies retrospectively in batch.
Further assessment of the tumor-associated immune microenvironment will measure: the expression of HLA class I, HLA class II, TAP and b2-microglobulin, the expression of PD-L1, at the mRNA (ISH) and protein (IHC) level, the expression of known tumor-associated antigens (TAA) and correlation with the TAA-specific T cell responses in the peripheral blood, the expression of PD-1 on different T cell subpopulations e.g. CD3, CD4, CD8, CD45RO and the expression of PD-L1 on immune cells, the co-expression of CD4, CD25, FOXP3 for identification of Tregs, combined with Ki67 (positive cells represent recently activated Tregs) and CD45RA (negative cells represent non-naïve, TCR-triggered Tregs), expression in T lymphocytes of TCR-signaling proteins e.g. Phospho-ZAP70, phospho-LAT, NFAT; expression of CD1c, CD11c, CD141, CD123, markers that define different dendritic cell subsets; CD68/CD163 (M1, M2 macrophages), CD20 (B lymphocytes), CD117 (mast cells), NKp46 (NK cells) and angiogenesis markers e.g. CD31, CD105, FasL, endothelin B receptor, ICAM1, VCAM1. |
Objetivos secundarios son: Supervivencia global, segunda supervivencia libre de progresión, control de la enfermedad y duración de respuesta según los criterios RECIST. Supervivencia libre de progresión a los 6 meses, segunda supervivencia libre de progresión y la respuesta clínica será también evaluada según irRECIST.
La tolerabilidad será también resumida por la frecuencia de modificación del régimen de tratamiento y las razones para interrumpir el tratamiento.
Se analizarán los linfocitos infiltrantes de tumores (TIL) sobre biopsias retrospectivas tumorales que se almacenarán en lotes.
Evaluaciones adicionales del microambiente tumoral medirán: La expresión de HLA clase 1 , HLA clase II, TAP y microglobulina, la expresión de PD-L1, niveles de expresión de PD-L1, niveles de mRNA (ISH) y proteína (IHC), la expresión de antígenos asociados a tumores (TAA) y la correlación con las respuestas de células T específicas para los TAA. En la sangre periférica, la expresión de PD-1 sobre diferentes subpoblaciones de células T, por ejemplo CD3, CD4, CD8, CD45RO y la expresión de PD-L1 sobre las células inmunológicas, la co-expresión de CD4, CD25, FOXP3 para la identificación of Tregs combinados con Ki67 (las células positivas representan células Treg recientemente activadas) y CD45RA (las células negativas representan células Tregs no vírgenes TCR-estimuladas), expresión en los linfocitos T de la proteína de señalización de TCR, por ejemplo, fosfo-ZAP70, fosfo-LAT, NFAT; expresión de CD1c, CD11c, CD141, CD123, marcadores que definen diferentes subpoblaciones de células dendríticas; CD68/CD163 (macrófagos M1, M2), CD20 (linfocitos B), CD117 (mastocitos), NKp46 (células NK) y marcadores de angiogenésis, por ejemplo, CD31, CD105, Fasl, receptor de la endotelina B, ICAM1, VCAM1. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Survival and safety is assessed continuously until study end; progression is assessed every 3 cycles during treatment, 9 weekly during years 1-2 and 6 until year 5. The assessment of the tumor-associated immune microenvironment will be performed in formalin-fixed, paraffin-embedded tumor samples and blood samples at baseline, pre-cycle 3 and at time of progression (if feasible). |
| La supervivencia y la seguridad se evaluarán continuamente hasta que finalice el estudio; La progresión se evaluará cada 3 ciclos durante el tratamiento, cada 9 semanas durante los años 1-2 y hasta el 5º año. La evaluación del microambiente inmunológico asociado al tumor será llevado a cabo en muestras del tumor fijadas en formalina y embebidas en parafina y en muestras de sangre en el momento de iniciar el estudio, basal, antes del ciclo 3 y en el momento de la progresión (si es factible). |
|
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Partially blinded for ASA administration (patient and local staff blinded) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 15 |
| 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 |
| Austria |
| Belgium |
| Denmark |
| France |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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