E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or Metastatic Solid Tumors including EGFR-mutated Non-Small Cell Lung Cancer. |
Tumores sólidos avanzados o metastásicos, incluido el cáncer de pulmón no microcítico con mutaciones en el gen EGFR. |
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E.1.1.1 | Medical condition in easily understood language |
Advanced or Metastatic Solid Tumors including EGFR-mutated Non-Small Cell Lung Cancer. |
Tumores sólidos avanzados o metastásicos, incluido el cáncer de pulmón no microcítico con mutaciones en el gen EGFR. |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 objectives are to assess anti-tumor activity (objective response rate [ORR]) (Cohorts 1, 2, and 3) and to evaluate the safety (Cohort 4) of amivantamab SC-CF via manual injection. |
Los objetivos principales son evaluar la actividad antitumoral (tasa de respuesta global [TRG]) (cohortes 1, 2 y 3) y evaluar la seguridad (cohorte 4) de amivantamab CF-SC mediante inyección manual. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess safety and additional measures of anti-tumor activity (Cohorts 1, 2, and 3) and to characterize the PK of amivantamab-SC-CF (Cohorts 1, 2, and 3). In Cohort 4 only, patient-reported outcomes (PROs) will be utilized to characterize participants’ experience with both formulations. |
Los objetivos secundarios son evaluar la seguridad y otras mediciones adicionales de la actividad antitumoral (cohortes 1, 2 y 3) y caracterizar la FC de amivantamab-CF-SC (cohortes 1, 2 y 3). Solo en la cohorte 4 se utilizarán los resultados comunicados por el paciente (PRO) para caracterizar la experiencia de los pacientes con ambas formulaciones. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age 1. Be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent. Type of Participant and Disease Characteristics 2. Participant must have histologically or cytologically confirmed, locally advanced or metastatic, NSCLC, characterized at the time of locally advanced or metastatic disease diagnosis. Additional Cohort specific disease requirements include: Cohorts 1 and 3: EGFR Exon19del or L858R mutation Cohort 2: EGFR Exon 20ins mutation EGFR Exon19del or Exon 21 L858R mutation (Cohort 1 and 3) or EGFR Exon 20 insertion mutation (Cohort 2) must have been identified as determined by an FDA-approved or other validated test of either ctDNA or tumor tissue in a CLIA certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the US). A copy of the initial test report documenting the EGFR mutation must be included in the participant records and a deidentified copy must also be submitted to the sponsor. 3. Have at least 1 measurable lesion, according to RECIST v1.1. If the only target lesion has been previously irradiated, it must show signs of disease progression since radiation was completed. Prior Malignancies 4. May have a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s) (see Appendix 12 of the Protocol on Allowed Recent Second or Prior Malignancies for details). Prior Therapy Restrictions or Requirements 5. Cohort-specific requirements with regards to prior therapy are as follows: Cohort 1 and 2: Participant should not have received any prior systemic therapy for metastatic NSCLC. Cohort 2: Participant should not have received any prior systemic therapy for metastatic NSCLC. However, prior monotherapy with an approved EGFR TKI targeting common EGFR mutations as first-line therapy for the treatment of locally advanced or metastatic disease is allowed, if: 1) treatment duration did not exceed 8 weeks; 2) lack of disease response was documented radiographically 3) associated toxicities have resolved to baseline; and 4) the EGFR TKI was discontinued at least 2 weeks or 4 half-lives prior to treatment initiation at C1D1, whichever is longer. Prior therapy with EGFR TKI agents targeting Exon20ins mutations (eg, TAK788/mobocertinib or poziotinib), is not allowed. Cohort 3: Participant should have progressed on or after osimertinib monotherapy as the immediate prior line of systemic therapy. Osimertinib must have been administered as the first EGFR TKI for metastatic disease or as the second TKI after prior treatment with first- or second-generation EGFR TKI. Cohort 4: Participants need to currently be on an amivantamab IV Q2W regimen without dose reduction (1,050 mg or 1,400 mg depending on weight) as part of standard of care for at least 3 months, an expanded access program, or as a rollover from a long-term extension prior amivantamab Q2W study. No washout is required between IV and SC-CF administration. 6. Toxicities from prior anticancer therapy, if any, must have resolved to CTCAE Version 5.0 Grade 1 or baseline level (except for other toxicities as indicated in inclusion criteria 8, alopecia [any grade], Grade ≤2 peripheral neuropathy, and Grade <2 hypothyroidism stable on hormone replacement). For Cohort 4 only: Amivantamab related toxicities that are stable and deemed tolerable by the investigator and patient are not exclusionary. Performance Status 7. Participant must have ECOG status of 0 or 1. Refer to Appendix 9 of the Protocol: Eastern Cooperative Oncology Group (ECOG) Performance Status. Renal, Hepatic and Hematological Function 8. Participant must demonstrate adequate organ and bone marrow function required for safe administration of the cohort-specific regimen, without history of red blood cell transfusion or platelet transfusion within 7 days prior to the date of the laboratory test, as follows: Cohorts 1 and 4 (chemotherapy-free regimens): a. Hemoglobin ≥9 g/dL b. Absolute neutrophil count ≥1.5x109/L, without use of granulocyte colony stimulating factor (G-CSF) within 10 days prior to the date of the test c. Platelets ≥75x109/L d. ALT and AST ≤3xULN if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases. e. Total bilirubin ≤1.5xULN (participants with Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits) f. eGFR >50 mL/min as measured or calculated by MDRD (Appendix 11: Formulas for Estimating Glomerular Filtration Rate Using Modified Diet in Renal Disease Formula [in mL/min])
For full list of inclusion criteria please refer to the Protocol (pages 43-47). |
Edad 1. Tener ≥18 años de edad (o la edad legal de consentimiento en la jurisdicción en la que se lleva a cabo el estudio) en el momento del consentimiento informado. Tipo de participante y características de la enfermedad - El paciente debe tener un cáncer de pulmón no microcítico (CPNM), localmente avanzado o metastásico, confirmado histológicamente o citológicamente, caracterizado en el momento del diagnóstico de la enfermedad localmente avanzada o metastásica. Otros requisitos específicos de la enfermedad de la cohorte son los siguientes: Cohortes 1 y 3: deleción en el exón 19 o mutación L858R del receptor del factor de crecimiento epidérmico (EGFR); cohorte 2: mutación del exón 20ins del EGFR, mutación por delección del exón 19 del EGFR o mutación del exón 21 L858R del EGFR (cohorte 1 y 3) o mutación del exón 20ins del EGFR (cohorte 2) previamente identificadas mediante una prueba aprobada por la Administración de Alimentos y Medicamentos de los Estados Unidos (FDA) o bien mediante otra prueba validada del ácido desoxirribonucleico tumoral circulante (ADNtc) o del tejido tumoral en un laboratorio certificado por las enmiendas para la mejora de los laboratorios clínicos (CLIA) (centros en los Estados Unidos [EE.UU.]) o un laboratorio local acreditado (centros fuera de los EE.UU.). Se debe incluir una copia del informe de la prueba inicial que documenta la mutación en el EGFR en los expedientes de los pacientes, así como también se debe enviar al promotor una copia desidentificada. - Tener al menos 1 lesión mensurable, según los Criterios de Evaluación de la Respuesta en Tumores Sólidos (RECIST) versión 1.1. Si la única lesión objetivo ha sido irradiada previamente, debe mostrar signos de progresión de la enfermedad desde que se completó la radiación. - Tener una segunda neoplasia maligna anterior o concurrente (distinta de la enfermedad en estudio) cuya evolución natural o cuyo tratamiento probablemente no interfiera con los criterios de valoración de seguridad del estudio o la eficacia de los tratamientos del estudio. - Presentar funciones orgánicas adecuadas (renales, hepáticas, hematológicas, de coagulación y cardíacas). - El paciente debe tener un estado funcional de 0 o 1 según la escala del Grupo Oncológico Cooperativo de la Costa Este de los Estados Unidos (ECOG). - La paciente debe comprometerse a no donar óvulos (ovocitos) ni a congelarlos para usos futuros con fines de reproducción asistida durante el estudio y durante un periodo de 6 meses después de la última dosis del tratamiento del estudio. Las pacientes deben considerar la conservación de los óvulos antes del tratamiento del estudio, ya que los tratamientos contra el cáncer pueden afectar a la fertilidad. |
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E.4 | Principal exclusion criteria |
Medical Conditions 1. Participant has an uncontrolled illness, including but not limited to: a. Uncontrolled diabetes b. Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week prior to starting study treatment] or diagnosed or suspected viral infection). c. Active bleeding diathesis d. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of study treatment e. Psychiatric illness or any other circumstances (including social circumstances) that would limit compliance with study requirements f. Any ophthalmologic condition that is clinically unstable 2. Participant has a medical history of ILD, including drug induced ILD or radiation pneumonitis 3. Participant has a history of hypersensitivity to any excipients of the investigational products to be used in their enrolment cohort 4. Participant has a history of clinically significant cardiovascular disease including, but not limited to: a. Diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to the first dose of study treatment(s), or any of the following within 6 months prior to the first dose of study treatment(s): myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots, are not exclusionary. b. Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate). c. Uncontrolled (persistent) hypertension: systolic blood pressure >160 mmHg; diastolic blood pressure >100 mmHg d. Congestive heart failure defined as NYHA class III-IV or hospitalization for CHF (any NYHA class) within 6 months of treatment initiation at C1D1 e. Pericarditis/clinically significant pericardial effusion f. Myocarditis g. Baseline LVEF below the institution’s lower limit of normal at screening, as assessed by echocardiogram or MUGA scan. 5. Participant had major surgery (eg, requiring general anesthesia), excluding placement of vascular access or tumor biopsy, or had significant traumatic injury within 4 weeks before signing the ICF, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study. Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate. 6. Participant has uncontrolled tumor-related pain: Symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) should be treated more than 7 days prior to the treatment initiation at C1D1. Disease Characteristics 7. Participant has received radiotherapy for palliative purposes less than 7 days prior to treatment initiation at C1D1. 8. Participant has symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study. Participants who have received definitive radiation or surgical treatment for symptomatic or unstable brain metastases and have been clinically stable and asymptomatic for at least 2 weeks before Screening are eligible, provided they have been either off corticosteroid treatment or are receiving low-dose corticosteroid treatment (≤10 mg/day prednisone or equivalent) for at least 2 weeks prior to treatment allocation. 9. Participant has a history of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation. Prior/Concomitant Therapy or Clinical Study Experience 10. Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before the planned first dose of study treatment. 11. Participant has received a live or live attenuated vaccine within 3 months before Cycle 1 Day 1. The seasonal influenza vaccine and non-live vaccines against COVID 19 are not exclusionary. 12. Cohorts 1, 3, and 4 (regimens potentially including lazertinib): Participant is currently receiving medications or herbal supplements known to be potent CYP3A4/5 inducers and is unable to stop use for an appropriate washout period prior to Cycle 1 Day 1. Other Exclusions 13. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise well-being) or that could prevent, limit, or confound the protocol-specified assessments
For full list of exclusion criteria please refer to the Protocol (pages 47-50). |
Condiciones Médicas - El paciente cuenta con una historia clínica de enfermedad pulmonar intersticial (EPI), incluida una EPI inducida por fármacos o una neumonitis por radiación. - El paciente tiene antecedentes de hipersensibilidad a cualquiera de los excipientes de los productos en investigación que se utilizarán en su cohorte de inscripción. - El paciente ha recibido una vacuna elaborada con microbios vivos o atenuada dentro de los 3 meses anteriores al día 1 del ciclo 1. La vacuna contra la gripe estacional y las vacunas no vivas contra la enfermedad del Coronavirus 19 (COVID-19) no son excluyentes. - Cohortes 1, 3 y 4 (pautas posológicas que pueden incluir lazertinib): el paciente recibe actualmente medicación o suplementos herbarios que se sabe que son potentes inductores del citocromo (CYP3A4/5) y no puede dejar de usarlos durante un periodo de reposo apropiado previo al día 1 del ciclo 1. - Otra enfermedad hepática clínicamente activa de origen infeccioso. - El paciente tiene antecedentes de una enfermedad cardiovascular clínicamente significativa, incluidos, entre otros: a. Diagnóstico de trombosis venosa profunda o embolia pulmonar en el plazo de 1 mes antes de la administración de la primera dosis del tratamiento del estudio, o diagnóstico de cualquiera de los siguientes en los 6 meses anteriores a la administración de la primera dosis del tratamiento del estudio: infarto de miocardio, angina inestable, ictus, accidente isquémico transitorio, injerto anastomótico coronario/en arteria periférica o cualquier síndrome coronario agudo. Las trombosis clínicamente no significativas, como los coágulos no obstructivos asociados a catéteres, no son excluyentes. b. Intervalo QT corregido prolongado según el método Fridericia (QTcF) superior a (>) 480 milisegundos (mseg), arritmia cardíaca clínicamente significativa o enfermedad electrofisiológica (por ejemplo, colocación de desfibrilador cardioversor implantable o fibrilación auricular con frecuencia no controlada). c. Hipertensión no controlada (persistente): presión arterial sistólica de > 160 milímetros de mercurio (mmHg); presión arterial diastólica de > 100 mmHg. d. Insuficiencia cardíaca congestiva de clase III-IV, según la Asociación Cardiológica de Nueva York (NYHA) u hospitalización por insuficiencia cardíaca congestiva (cualquier clase de la NYHA) en los 6 meses siguientes al inicio del tratamiento el día 1 del ciclo 1 (D1C1). e. Pericarditis o derrame pericárdico clínicamente significativo. f. Miocarditis. g. Fracción de eyección del ventrículo izquierdo (FEVI) en el momento de referencia por debajo del límite inferior de la normalidad de la institución en el momento de la selección, evaluada mediante ecocardiograma o ventriculografía nuclear (MUGA). - El paciente tiene metástasis cerebrales sintomáticas. Un paciente con metástasis cerebrales asintomáticas o previamente tratadas y estables puede participar en este estudio. Los pacientes que han recibido radiación definitiva o tratamiento quirúrgico para metástasis cerebrales sintomáticas o inestables, y han sido clínicamente estables y asintomáticos durante al menos 2 semanas antes de la selección son elegibles, siempre que no hayan recibido tratamiento con corticosteroides o estén recibiendo dosis bajas de tratamiento con corticosteroides (≤ 10 mg/día de prednisona o equivalente) durante al menos 2 semanas antes de la asignación del tratamiento. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Cohorts 1, 2, and 3 - ORR (INV) Cohort 4 - Incidence and severity of adverse events and clinical laboratory abnormalities |
Cohorte 1, 2 y 3 -ORR (INV) Cohorte 4 - Incidencia y severidad de eventos adversos y anormalidades de laboratorio clínico |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort 1,2,3: The primary analysis of primary endpoints for Cohorts 1, 2, and 3 will be performed after all participants have completed at least 3 disease assessments (unless they withdrew consent or died prior). Cohort 4: The primary analysis of primary endpoints will be performed 3 months after the last participant in that cohort received the first dose (i.e., once all enrolled patients have completed at least 3 cycles of treatment or discontinued prior). The final analysis of primary and secondary endpoints as well as the analysis of exploratory endpoints will be performed after the last participant in that cohort completed the Follow-up Phase. |
Cohorte1,2,3:el análisis de los criterios de valoración principales para las cohortes1,2y3 se realizará después de los participantes hayan completado al menos 3 evaluaciones de la enfermedad (a menos que hayan retirado el consentimiento o hayan fallecido).Cohorte 4:el análisis de los criterios de valoración principales se realizará 3 meses después de que el último participante de esa cohorte haya recibido la primera dosis (una vez que todos los pacientes inscritos hayan completado al menos 3 ciclos de tratamiento o lo hayan interrumpido antes). El análisis final de los criterios de valoración primarios y secundarios, así como el análisis de los criterios de valoración exploratorios, se realizará después de que el último participante de esa cohorte haya completado la fase de seguimiento. |
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E.5.2 | Secondary end point(s) |
Cohorts 1, 2, and 3 - Incidence and severity of adverse events and clinical laboratory abnormalities - ORR (ICR) - DoR - TTR - CBR (INV) - PFS - OS - Serum Ctrough of amivantamab on Cycle 2 Day 1 - Serum amivantamab concentrations and serum anti-amivantamab antibodies (Cohorts 1, 2, and 3) - Plasma lazertinib concentrations (Cohorts 1 and 3) - The presence or absence of anti-rHuPH20 antibodies
Cohort 4 - Incidence and severity of adverse events and clinical laboratory abnormalities - Modified TASQ-IV - Modified TASQ-SC - PGIC - PGIS |
Cohortes 1, 2 y 3 - Incidencia y severidad de eventos adversos y anormalidades de laboratorio clínico - ORR (ICR) - DoR - TTR - CBR (INV) - PFS - OS
- Concentración sérica de amivantamab en el día 1 del ciclo 2 - Concentraciones de amivantamab en suero y anticuerpos anti-amivantamab en suero (cohortes 1, 2 y 3) - Concentraciones plasmáticas de lazertinib (Cohortes 1 y 3) - La presencia o ausencia de anticuerpos anti-rHuPH20
Cohorte 4 - Incidencia y severidad de eventos adversos y anormalidades de laboratorio clínico - TASQ-IV modificado - TASQ-SC modificado - PGIC - PGIS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort 1,2,3: The primary analysis of secondary endpoints for Cohorts 1, 2, and 3 will be performed after all participants have completed at least 3 disease assessments (unless they withdrew consent or died prior). Cohort 4: The primary analysis of secondary endpoints will be performed 3 months after the last participant in that cohort received the first dose (i.e., once all enrolled patients have completed at least 3 cycles of treatment or discontinued prior). The final analysis of primary and secondary endpoints as well as the analysis of exploratory endpoints will be performed after the last participant in that cohort completed the Follow-up Phase. |
Cohorte1,2,3:el análisis de los criterios de valoración secundarios para las cohortes1,2y3 se realizará después de que los participantes hayan completado al menos 3 evaluaciones de la enfermedad(a menos que hayan retirado el consentimiento o hayan fallecido).Cohorte 4: l análisis de los criterios de valoración secundarios se realizará 3 meses después de que el último participante de esa cohorte haya recibido la primera dosis(una vez que todos los pacientes inscritos hayan completado al menos 3 ciclos de tratamiento o lo hayan interrumpido antes). El análisis final de los criterios de valoración primarios y secundarios, así como el análisis de los criterios de valoración exploratorios, se realizará después de que el último participante de esa cohorte haya completado la fase de seguimiento. |
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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 | No |
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) | 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 | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
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 |
Australia |
Brazil |
China |
India |
Israel |
Japan |
Korea, Democratic People's Republic of |
Malaysia |
Taiwan |
United States |
Spain |
Turkey |
United Kingdom |
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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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |