E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Crohn's disease |
Enfermedad de Crohn |
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E.1.1.1 | Medical condition in easily understood language |
Crohn's disease |
Enfermedad de Crohn |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011402 |
E.1.2 | Term | Crohn's disease (colon) |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 objective of the study is to characterize the dose-response relationship of CP-690,550 in inducing clinical remission in subjects with moderate to severe Crohn?s disease and to select effective doses. |
El objetivo principal del estudio es definir la relación dosis-respuesta de CP-690,550 en la inducción de la remisión clínica en sujetos con enfermedad de Crohn de moderada a grave y seleccionar la dosis eficaz. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of CP-690,550 induction therapy in subjects with moderate to severe Crohn?s disease. ? To characterize the dose-response relationship of CP-690,550 in inducing clinical response in subjects with moderate to severe Crohn?s disease. ? To characterize the pharmacokinetics of CP-690,550 in subjects with moderate to severe Crohn?s disease. ? To evaluate the effect of CP-690,550 on quality of life in subjects with moderate to severe Crohn?s disease. ? To evaluate the effect of CP-690,550 on CRP and fecal calprotectin. |
? Evaluar la seguridad y la tolerabilidad de CP-690,550 como tratamiento de inducción en sujetos con enfermedad de Crohn de moderada a grave. ? Describir la relación dosis-respuesta de CP-690,550 en la inducción de remisión clínica en sujetos con enfermedad de Crohn de moderada a grave. ? Describir la farmacocinética de CP-690,550 en sujetos con enfermedad de Crohn de moderada a grave. ? Evaluar el efecto de CP-690,550 sobre la calidad de vida en sujetos con enfermedad de Crohn de moderada a grave. ? Evaluar el efecto de CP-690,550 en la PCR y la calprotectina fecal. |
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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 |
Molecular Profiling Supplement |
Suplemento de Perfil Molecular |
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E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator?s study team before subjects are included in the study. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: 1. Male or female subjects between the ages of ?18 and ?75 years at screening. 2. Subjects with clinical diagnosis of Crohn?s disease (CD) for at least 6 months prior to screening. 3. Subjects with active moderate to severe ileal, ileocolic, or colonic CD defined by a baseline score of Crohn?s Disease Activity Index (CDAI) of ?220 to ?450 at baseline. 4. Subjects with a history of inadequate treatment response or intolerance (as defined by the Investigator) to at least one of the following therapies for Crohn?s disease: ? Corticosteroids. ? Azathioprine/6-Mercaptopurine. ? Methotrexate. ? Anti-TNF therapy (Infliximab; Adalimumab; Certolizumab pegol). 5. Subjects currently receiving any of the following treatments for Crohn?s disease are eligible provided they are on stable dose for designated period of time and throughout the study: ? Oral 5-ASA or sulfasalazine stable dose for at least 4 weeks prior to baseline. ? Oral corticosteroids (prednisolone up to 30 mg/day; budesonide up to 9 mg/day) stable dose for at least 2 weeks prior to baseline. ? Chronic treatment for Crohn?s disease with antibiotics (e.g. metronidazole, ciprofloxacin, rifaximin) stable dose for at least 2 weeks prior to baseline. ? Rectally administered formulation of corticosteroids or 5-ASA stable dose for at least 2 weeks prior to baseline. 6. Subjects with presence of ulceration at screening/baseline colonoscopy as defined by the Simple Endoscopic Score for Crohn?s Disease (SES-CD): aphthous ulcers (0.1 to 0.5 cm), large ulcers (0.5 to 2 cm), or very large ulcers (>2 cm). 7. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by all of the following: ? A negative QuantiFERON®-TB Gold In-Tube test or, if unavailable, a Mantoux Purified Protein Derivative skin test, concentration as per local medical standard of practice, result of <5 mm of induration, performed within the 3 months prior to screening. [It is recommended that subjects with a history of Bacille Calmette Guérin (BCG) vaccination be tested with the QuantiFERON®-TB Gold In-Tube test.]. ? A chest radiograph taken at or within the 3 months prior to screening, without changes suggestive of active TB infection as determined by a qualified radiologist. ? No history of either untreated or inadequately treated latent or active TB infection. ? If a subject has previously received an adequate course of therapy for either latent (9 months of isoniazid in a locale where rates of primary multi-drug resistant TB infection are <5% or an acceptable alternative regimen) or active (acceptable multi-drug regimen) TB infection, neither a PPD test nor a QuantiFERON® -TB Gold In-Tube test need be obtained, but a chest radiograph must still be obtained if not done so within the prior 3.months. Documentation of adequate treatment for TB will be obtained prior to first dose of study drug. ? A subject who is currently being treated for active TB infection is to be excluded. ? A subject who is currently being treated for latent TB infection can only be enrolled with confirmation of current incidence rates of multi-drug resistant TB infection in the locale, documentation of an adequate treatment regimen, and with prior approval by the Sponsor. 8. Women of childbearing potential must test negative for pregnancy prior to study enrolment. 9. Sexually active females of childbearing potential are required to use adequate contraceptive methods during the study period and until completion of the follow-up procedures. (Further description of the requirements and a list of contraceptives considered effective and acceptable for use in this trial are found in Section 4.4 Life Style Guidelines in the protocol). 10. Subjects receiving non-prohibited concomitant medications for any reason, must be on a stable regimen, which is defined as not starting a new medication or changing dosage of a current medication within 7 days or 5 half-lives (whichever is longer) prior to baseline and for the duration of the study. 11. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. 12. Evidence of a personally signed and dated informed consent document(s) indicating that the subject has been informed of all pertinent aspects of the study. |
1.Varones o mujeres de edad ?18 y ? 75 años en el momento de la selección. 2.Sujetos con diagnóstico clínico de enfermedad de Crohn desde al menos 6 meses antes de la selección. 3.Sujetos con EC ileal, ileocólica o cólica activa de moderada a grave, que se define por una puntuación basal del Índice de actividad de la enfermedad de Crohn (CDAI) de ?220 a ?450. 4.Sujetos con antecedentes de respuesta insuficiente o intolerancia (definidas por el investigador) como mínimo a uno de los siguientes tratamientos para la enfermedad de Crohn: ?Corticoides ?Azatioprina/6-mercaptopurina ?Metotrexato ?Tratamiento anti-TNF (infliximab; adalimumab; certolizumab pegol) 5.Los sujetos que reciban actualmente alguno de los tratamientos siguientes para la enfermedad de Crohn pueden ser elegidos siempre que mantengan una dosis estable durante el periodo de tiempo especificado y durante todo el estudio: ?Dosis estables de 5-ASA o sulfasalazina por vía oral durante al menos 4 semanas antes de la visita basal. ?Dosis estables de corticoides orales (hasta 30 mg de prednisolona al día; hasta 9 mg de budesonida al día) durante al menos 2 semanas antes de la visita basal. ?Tratamiento crónico para la enfermedad de Crohn con antibióticos (por ejemplo, metronidazol, ciprofloxacino o rifaximina) en dosis estables durante al menos 2 semanas antes de la visita basal. ?Dosis estable de una formulación de corticoides o 5-ASA para administración rectal durante al menos 2 semanas antes de la visita basal. 6.Sujetos con úlceras en la colonoscopia de selección/basal según la puntuación endoscópica simple para la enfermedad de Crohn (SES-CD): úlceras aftosas (0,1 a 0,5 cm), úlceras grandes (0,5 a 2 cm) o úlceras muy grandes (>2 cm) (apéndice 2). 7.Ausencia de indicios de infección activa, latente o mal tratada por Mycobacterium tuberculosis (TB), que se define por todo lo siguiente: ?Una prueba QuantiFERONGold®-TB Gold In Tube negativa o, en caso de no disponer de ella, una prueba cutánea de Mantoux con derivado proteico purificado (PPD), utilizando la concentración indicada por la práctica médica local, con un resultado de <5 mm de induración, realizada en los tres meses anteriores a la selección. [Se recomienda analizar a los pacientes con antecedentes de vacunación con el bacilo de Calmette Guérin (BCG) con la prueba QuantiFERON®-TB Gold In-Tube]. ?Una radiografía de tórax, realizada en los tres meses anteriores a la visita de selección, sin alteraciones indicativas de TB activa según la opinión de un radiólogo cualificado. ?Ausencia de antecedentes de infección TB activa o latente no tratada o mal tratada. ?Si un sujeto ya ha recibido un ciclo suficiente de tratamiento por una infección TB latente (isoniazida durante 9 meses en un lugar en el que las tasas de multirresistencia primaria sean < 5 % u otro régimen aceptable) o activa (tratamiento multifarmacológico aceptable), no será necesario realizar una prueba con PPD ni una prueba QuantiFERON®-TB Gold In-Tube, pero sí una radiografía de tórax en caso de no haberse realizado una en los tres meses precedentes. La documentación del tratamiento adecuado de la TB se obtendrá antes de la primera dosis del fármaco del estudio. ?Se excluirá a los sujetos que estén recibiendo tratamiento por una TB activa. ?Un sujeto que esté en tratamiento por una TB latente solo podrá participar con una confirmación de las tasas de incidencia actualizadas de TB multirresistente en la región, con documentación de un régimen de tratamiento adecuado y con la aprobación previa del promotor. 8.Las mujeres en edad fértil deberán tener un resultado negativo en una prueba de embarazo antes de ser incluidas en el estudio. 9.Las mujeres en edad fértil sexualmente activas deberán utilizar métodos anticonceptivos adecuados durante el estudio y hasta la finalización de los procedimientos de seguimiento. (En el apartado 4.4 Normas relativas al modo de vida, se ofrece una descripción más detallada de los requisitos y una lista de anticonceptivos que se consideran eficaces y aceptables para uso en este ensayo). 10.Los sujetos que reciban, por el motivo que sea, algún medicamento concomitante que no esté prohibido, deberán mantener un régimen estable, es decir, no podrán empezar a tomar ningún fármaco nuevo ni cambiar la dosis en 7 días o el período correspondiente a 5 semividas (lo que suponga más tiempo) antes de la visita basal y durante todo el estudio. 11.Sujetos dispuestos a cumplir las visitas programadas, el plan de tratamiento, los análisis clínicos y otros procedimientos del estudio, y capaces de hacerlo. 12.Prueba de un documento de consentimiento informado, firmado y fechado personalmente en el que se indique que el sujeto ha sido informado de todos los aspectos pertinentes del estudio. |
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E.4 | Principal exclusion criteria |
1.Diagnosis of indeterminate colitis,ulcerative colitis (UC), or findings suggestive of UC. 2.Subjects diagnosed with Crohn?s disease (CD) but without prior exposure to treatment (i.e treatment-naïve) or having failed or been intolerant to treatment solely with 5-ASA containing compounds.3.Subjects receiving following treatment for CD: Azathioprine, 6-mercaptopurine or methotrexate (MTX) within 2 weeks prior to baseline (PTB); Anti-TNF? therapy within 8 weeks prior to baseline; Interferon therapy within 8 weeks PTB; Cyclosporine, mycophenolate or tacrolimus within 8 weeks prior to baseline; i.v.corticosteroids within 2 weeks PTB. 4.Subjects who have previously received natalizumab or any anti-adhesion molecule, within 1 year PTB. 5.Subjects who have previously participated in any study of CP-690,550. 6.Participation in other studies within 3 months before current study begins and/or during study. 7.History of symptomatic obstructive strictures or an active ostomy. 8.History of total colectomy, extensive small bowel resection(>100cm) or short bowel syndrome. 9.History of bowel surgery within 6 months PTB. 10.Subjects likely to require any type of surgery during the study period. 11.Fecal culture/toxin assay indicating presence of pathogenic infection. 12.Presence of active (draining) fistulae, intrabdominal or perineal collection or abscess (Subjects with prior history of fistulae including entero-cutaneous, entero-enteric, entero-vesicular,entero-vaginal, or perineal fistulae or abdominal or perineal abscess will require MRI of abdomen / pelvis prior to randomization) 13.Subjects on elemental diet used for treating CD within 7days PTB. 14. Subjects with blood dyscrasias at screening, including confirmed: Hemoglobin levels <9.0g/dL or hematocrit <30%; An absolute white blood cell(WBC)count of <3.0x10 to the power of 9/L (<3000/mm3) or absolute neutrophil count of <1.2x10 to the power of 9/L (<1200/mm3); Thrombocytopenia, as defined by a platelet count <100x10 to the power of 9/L(<100,000/mm3). 15. Subjects with evidence of or suspected liver disease i.e. liver injury due to MTX or primary sclerosing cholangitis.16.Subjects with estimated GFR ?40 ml/min at screening, based on Cockcroft-Gault calculation. 17.Subjects with total bilirubin,AST or ALT more than 1.5 times upper limit of normal at screening. 18.Subjects with current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, GI,metabolic, endocrine, pulmonary, cardiac or neurological disease.19.Subjects who have been vaccinated with any live or attenuated virus vaccine within 6 weeks PTB or scheduled to receive live virus vaccination during study period &for 6 weeks after last dose of study drug. 20.Subjects with history of any lymphoproliferative disorder, history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs & symptoms suggestive of current lymphatic disease. 21.Subjects with clinically significant infections currently or within 6 months PTB, a history of any infection requiring antimicrobial therapy within 2 weeks PTB or history of any infection otherwise judged by the investigator to have potential for exacerbation by participation in study. 22.Subjects with a history of more than one episode of herpes zoster (HZ), a history of disseminated HZ or disseminated herpes simplex. 23.Subjects with prior treatment with lymphocyte-depleting agents/therapies. 24.Subjects with any condition possibly affecting oral drug absorption. 25.Women who are pregnant or lactating,or planning pregnancy during the study period. 26.History of alcohol or drug abuse with less than 6 months of abstinence PTB. 27.Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results. 28.Subjects with history of blood donation in excess of 500mL within 8 weeks PTB. 29.Subjects with history of blood transfusion within 4 weeks PTB. 30.Subjects with a first-degree relative with a hereditary immunodeficiency. 31.Subjects with any malignancies or with a history of malignancies with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin. 32. Significant trauma or major surgery within 4 weeks of screening visit. 33.Subjects infected with human immunodeficiency virus(HIV) or hepatitis B or C viruses. 34.Subjects receiving prohibited concomitant medications. 35. Subjects who, in the opinion of investigator or Pfizer, will be uncooperative or unable to comply with study procedures. 36. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase risk with investigational product administration or may interfere with interpretation of study results & would make the subject inappropriate for entry into this study. 37.Subjects who are study site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial. |
1.Diagnóstico de colitis indeterminada, colitis ulcerosa (CU) o hallazgos clínicos que indiquen CU. 2.Sujetos con diagnóstico de enfermedad de Crohn, pero sin exposición previa al tratamiento (es decir, sin tratamiento previo) o haber fracasado o ser intolerante sólo a compuestos que contengan 5-ASA. 3.Sujetos que reciban el siguiente tratamiento para la enfermedad de Crohn: ?Azatioprina, 6-mercaptopurina o metotrexato en las 2 semanas previas a la visita basal. ?Tratamiento anti-TNF? en las 8 semanas previas a la visita basal. ?Tratamiento con interferón en las 8 semanas previas a la visita basal. ?Ciclosporina, micofenolato o tacrolimús en las 8 semanas previas a la visita basal. ?Corticoides intravenosos en las 2 semanas previas a la visita basal. 4.Sujetos que hayan recibido con anterioridad natalizumab o cualquier fármaco que inhiba la adherencia molecular en el año anterior a la visita basal. 5.Sujetos que hayan participado previamente en un estudio de CP-690,550. 6.Participación en otros estudios durante los 3 mes anteriores al inicio de este estudio o durante el mismo. 7.Antecedentes de estenosis obstructivas sintomáticas o una ostomía activa. 8.Antecedentes de colectomía total, resección del intestino delgado amplia (>100 cm) o síndrome del intestino corto. 9.Antecedentes de cirugía intestinal en los 6 meses previos a la visita basal. 10.Sujetos con probabilidades de necesitar cualquier tipo de cirugía durante el período del estudio.
En total son 37 criterios de exclusión, debido a la limitación de caracteres, se remite al protocolo apartado 4.2 |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects in clinical remission at week 8 as defined by a Crohn?s disease activity index (CDAI) score of less than 150 points. |
Proporción de sujetos en remisión clínica en la semana 8, que se define por una puntuación inferior a 150 puntos en el índice de actividad de la enfermedad de Crohn (CDAI). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The proportion of subjects in clinical remission at week 8 as defined by a Crohn?s disease activity index (CDAI) score of less than 150 points |
Proporción de sujetos en remisión clínica en la semana 8, que se define por una puntuación inferior a 150 puntos en el índice de actividad de la enfermedad de Crohn (CDAI). |
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E.5.2 | Secondary end point(s) |
The proportions of subjects in clinical remission (CDAI<150) at Week 2 and 4. The proportion of subjects achieving clinical response-70 at Week 2, 4, and 8 as defined by a decrease in CDAI score of at least 70 points from baseline. The proportion of subjects achieving clinical response-100 at Week 2, 4, and 8 as defined by a decrease in CDAI score of at least 100 points from baseline. The proportion of subjects achieving either clinical response-100 or clinical remission (CDAI<150) at Week 2, 4, and 8. CDAI scores over time. Serum CRP and fecal calprotectin levels over time. Plasma CP-690,550 concentration over time. |
?Proporción de pacientes en remisión clínica (CDAI <150) en las semanas 2 y 4. ?Proporción de sujetos que consiguen una respuesta clínica-70 en las semanas 2, 4 y 8, que se define por una reducción de la puntuación CDAI de al menos 70 puntos con respecto al valor basal. ?Proporción de sujetos que consiguen una respuesta clínica-100 en las semanas 2, 4 y 8, que se define por una reducción de la puntuación CDAI de al menos 100 puntos con respecto al valor basal. ?Proporción de sujetos que logran una respuesta clínica-100 o una remisión clínica (CDAI<150) en las semanas 2, 4 y 8. ?Puntuaciones CDAI a lo largo del tiempo. ?PCR y calprotectina fecal séricas a lo largo del tiempo. ?Concentración plasmática de CP-690,550 a lo largo del tiempo. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The proportions of subjects in clinical remission (CDAI<150) at week 2 and 4 The proportion of subjects achieving clinical response-70 at week 2, 4, and 8 as defined by a decrease in CDAI score of at least 70 points from baseline The proportion of subjects achieving clinical response-100 at week 2, 4, and 8 as defined by a decrease in CDAI score of at least 100 points from baseline The proportion of subjects achieving either clinical response-100 or clinical remission (CDAI<150) at week 2, 4, and 8 The proportions of subjects in clinical remission (CDAI<150) at week 2 and 4 CDAI scores over time Serum CRP and fecal calprotectin levels over time Plasma CP-690,550 concentration over time |
?Proporción de pacientes en remisión clínica (CDAI <150) en las semanas 2 y 4. ?Proporción de sujetos que consiguen una respuesta clínica-70 en las semanas 2, 4 y 8, que se define por una reducción de la puntuación CDAI de al menos 70 puntos con respecto al valor basal. ?Proporción de sujetos que consiguen una respuesta clínica-100 en las semanas 2, 4 y 8, que se define por una reducción de la puntuación CDAI de al menos 100 puntos con respecto al valor basal. ?Proporción de sujetos que logran una respuesta clínica-100 o una remisión clínica (CDAI<150) en las semanas 2, 4 y 8. ?Puntuaciones CDAI a lo largo del tiempo. ?PCR y calprotectina fecal séricas a lo largo del tiempo. ?Concentración plasmática de CP-690,550 a lo largo del tiempo. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | 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 | 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 | 49 |
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 |
Austria |
Bulgaria |
Canada |
Croatia |
Czech Republic |
France |
Germany |
Greece |
Hungary |
India |
Israel |
Japan |
Korea, Republic of |
Netherlands |
Norway |
Romania |
Slovakia |
South Africa |
Spain |
Sweden |
Ukraine |
United States |
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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
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EOT in all participating countries is defined as LSLV. EOT in a Member State of the EU is defined as time at which it is deemed that sufficient subjects have been recruited & completed the study as stated in regulatory application (ie, Clinical Study Application) ðics application in the Member State (MS). Poor recruitment (recruiting less than the anticipated number in the CTA) by a MS is not a reason for premature termination but is considered a normal conclusion to the study in that MS. |
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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 | 7 |
E.8.9.1 | In the Member State concerned days | 28 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 28 |