E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Functionnal impairment after acute ischemic stroke |
Deficiencia Funcional tras el ictus isquémico agudo. |
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E.1.1.1 | Medical condition in easily understood language |
Handicap in post stroke patients |
Minusvalía en pacientes tras el accidente cerebrovascular. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061256 |
E.1.2 | Term | Ischaemic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system 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 |
To assess the effect of 3-month treatment with F2695 (75 mg OD) on improving functional recovery in patients with moderate to severe motor deficits after an ischemic stroke |
Evaluar el efecto de 3 meses de tratamiento con F2695 (75 mg al día) para favorecer la recuperación funcional de pacientes con déficit motor moderado a grave por un ictus isquémico. |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of F2695 on: o Motor recovery, o Occurrence and recurrence of depression,
To evaluate the safety and tolerability of F2695 in patients with ischemic stroke. |
Evaluar el efecto del F2695 sobre: - la recuperación motriz; - la incidencia y la reincidencia de la depresión.
Evaluar la seguridad y la tolerabilidad del F2695 en pacientes con ictus isquémico. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Demographic Characteristics and Diagnostic criteria: To be included in the trial, patients admitted to stroke units should fulfil the following criteria: o Male or female patient, 18 to 80 years of age, inclusively, o Who had a confirmed acute ischemic stroke within the past 2 - 10 days , associated: o with an unilateral motor deficit (hemiparesis or hemiplegia), o with a National Institutes of Health stroke scale (NIHSS) motor score greater or equal to 5, o with a modified Rankin Scale (mRS) of 4 or 5, o Able and willing to comply with the site rehabilitation program requirements, o Woman of childbearing potential must have been using an effective method of contraception (defined as surgical or hormonal birth control, or intra-uterine device only), assessed by the investigator, for at least 2 months before selection in the study, and must accept to go on using it during the whole duration of the study and up to 1 month after the last dose of the study treatment, in order to avoid pregnancy while being exposed to the study treatment
Ethical /legal considerations: o Signed written informed consent to take part in the study obtained from the patient. In case of impossibility for the patient to sign the consent form, the consent is to be witnessed by a third party completely independent from the investigator and the sponsor. This witness will have to sign the consent form and the patient will have to sign the consent form once his condition permits , before the end of the study. o Affiliated to a social security system, or is a beneficiary (if applicable in the national regulation). |
Características demográficas y diagnóstico: Para participar en el estudio, el paciente debe encontrarse ingresado en una unidad de ictus y reunir todos los criterios siguientes: o Sexo masculino o femenino y edad comprendida entre los 18 y los 80 años inclusive. o Ictus isquémico agudo confirmado en los últimos 2-10 días, asociado: - con un déficit motor unilateral (hemiparesia o hemiplejia); - con una puntuación motriz mayor o igual a 5 en la Escala del Ictus de los National Institutes of Health (NIHSS); - con una puntuación de 4 ó 5 en la Escala de Rankin modificada (mRS). o Capacidad y voluntad de ceñirse a los requisitos del programa de rehabilitación del centro. o En el caso de las mujeres en edad fértil, utilización de un método anticonceptivo eficaz (esterilización quirúrgica, anticonceptivos hormonales o dispositivo intrauterino), a juicio del investigador, durante al menos 2 meses antes de la selección y compromiso de continuar utilizándolo durante todo el estudio y hasta que transcurra un mes de la última dosis del tratamiento, a fin de prevenir el embarazo durante la exposición al medicamento.
Aspectos ético-jurídicos: o Firma del documento de consentimiento informado para participar en el estudio. Si el paciente está incapacitado para firmarlo personalmente, el proceso de consentimiento deberá presenciarlo un testigo imparcial que sea totalmente ajeno al promotor y al equipo investigador. El testigo firmará en un primer momento el documento de consentimiento informado y el paciente lo firmará cuando se lo permita su estado, antes de que termine el estudio. o Afiliación a un régimen de la Seguridad Social o condición de beneficiario (según proceda en el sistema nacional de salud). |
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E.4 | Principal exclusion criteria |
- Disease-related criteria: o Patient with motor sequelae from a previous stroke, o Patient with pre-existing or concomitant deficit that could interfere with testing or clinical assessments, o Patient with aphasia preventing correct evaluation of motor and / or depression scales, o Patient with severe post-stroke condition (NIHSS score >20), o Patient with active depressive episode (MADRS score of more than 18 and / or a Clinical Global Impression scale in depression - CGI - Depression > 3), o Patient with evidence of intra-cerebral haemorrhage on brain MRI or CT scan, o Patient needing carotid surgery within 3 months.
- Previous or concomitant treatment-related criteria: o Patient having taken within the month preceding inclusion one or more of the following drugs: o antidepressant drugs belonging to the classes of SSRIs, SNRIs and TCAs (whatever the indication), o monoamine oxidase inhibitors or any other drug which may increase the risk of serotonin syndrome (tramadol, methylphenidate, triptans, propoxyphene, lithium...) o neuroleptic drugs, o alpha1-adrenoreceptor antagonists, o central nervous system stimulants (modafinil, methylphenidate, amphetamines...), o Patient with an history of intolerance or hypersensitivity to F2695, milnacipran or other SNRIs, SSRIs, or selective noradrenergic reuptake inhibitors, o Patient displaying criteria for psychoactive substance abuse or dependency (according to DSM-IV).
- Patient-related criteria: o Patient with severe cognitive impairment or dementia, o Patient presents an acute coronary syndrome, o Patient presenting cardiac rhythm disorder (including tachyarrhythmia) in the 3 months preceding the inclusion, o Patient presenting uncontrolled arterial hypertension or symptomatic postural hypotension, o Patient with history of myocardial infarction in the preceding 3 months, o Patient unable to safely swallow capsules, o Patient presenting disability (mRS > 1) prior to the current stroke (rheumatological diseases, sequelaes of traumatic diseases or from previous stroke injury...), o Patient with the following abnormal clinical laboratory test results: - Liver function test values (aspartate aminotransferase and/or alanine aminotransferase) greater than 3 times the upper limit of normal, - An estimated glomerular filtration rate (eGFR) < 60ml/min/1,73m2 o Patient with a history of coagulation or haemostasis disorders which the investigator deems incompatible with study implementation, o Patient with a history of narrow angle glaucoma, o Patients with a prior history of seizures/epilepsy (before the onset of stroke event), o Patient presenting with a severe acute or chronic disease which the investigator deems incompatible with study implementation. This includes evidence of malignancy or any significant or progressive disease (endocrine, respiratory, renal, hepatic, gastrointestinal, neurologic disease or infectious disease), o Patient liable not to comply with protocol instructions and/or with treatment (including rehabilitation therapy), in the investigator's opinion, o Male patients with history of obstructive voiding symptoms, including urinary retention, o For women patients: - pregnant, breast feeding or likely to become pregnant during the time of the study o women with childbearing potential not using effective contraception (defined as surgical or hormonal birth control, or intra-uterine device only). o positive serum ?-hCG pregnancy test at inclusion for females with childbearing potential. |
Criterios patológicos: o Secuelas motrices de un ictus anterior. o Déficit preexistente o concomitante que interfiera en las evaluaciones clínicas o los análisis de laboratorio. o Afasia que impida la correcta evaluación de las escalas de la función motriz o de la depresión. o Estado grave como consecuencia del ictus (NIHSS > 20). o Episodio depresivo activo (puntuación MADRS > 18 o puntuación > 3 en la escala de impresión clínica global [CGI] de la depresión). o Objetivación de hemorragia intracerebral en el TAC o la RMN encefálica. o Necesidad de cirugía de carótidas en los próximos 3 meses.
Criterios relacionados con los tratamientos previos o concomitantes: o Tratamiento, en el mes anterior a la inclusión, con los fármacos siguientes: - antidepresivos de la clase de los ISRS, los ISRN y los tricíclicos (por cualquier indicación); - inhibidores de la monoamina-oxidasa o cualquier otro fármaco que acentúe el riesgo de síndrome serotoninérgico (tramadol, metilfenidato, triptanos, dextropropoxifeno, litio, etc.); - neurolépticos; - antagonistas del receptor adrenérgico alfa-1; - estimulantes del sistema nervioso central (modafinilo, metilfenidato, anfetaminas, etc.). o Antecedentes de intolerancia o hipersensibilidad al F2695, al milnaciprán o a otros ISRN, ISRS o inhibidores selectivos de la recaptación noradrenérgica. o Criterios de abuso o dependencia de sustancias psicoactivas (según el DSM-IV).
Criterios relacionados con el paciente: o Deterioro cognitivo grave o demencia. o Síndrome coronario agudo. o Trastornos del ritmo cardíaco (incluida la taquiarritmia) en los 3 meses anteriores a la inclusión. o Hipertensión arterial incontrolada o hipotensión ortostática sintomática. o Antecedentes de infarto de miocardio en los últimos 3 meses. o Incapacidad de tragar cápsulas. o Discapacidad (mRS > 1) antes del ictus actual (reumatismos, secuelas de traumatismos o de un ictus anterior, etc.). o Las siguientes alteraciones analíticas: - valores de función hepática (concentración de aspartato-aminotransferasa o alaninaaminotransferasa) que tripliquen el límite superior de la normalidad; - índice de filtración glomerular estimado (IFGe) < 60 ml/min/1,73 m2. o Antecedentes de trastornos de la coagulación o de la hemostasia que el investigador estime incompatibles con la participación en el estudio. o Antecedentes de glaucoma de ángulo cerrado. o Antecedentes de convulsiones o epilepsia (antes del accidente cerebrovascular actual). o Enfermedad aguda o crónica grave que el investigador estime incompatible con la participación en el estudio; por ejemplo: neoplasia maligna o enfermedad degenerativa o importante (endocrina, respiratoria, renal, hepática, digestiva, neurológica o infecciosa). o Previsión de incumplimiento de las instrucciones del protocolo o del tratamiento (incluida la rehabilitación), a juicio del investigador. o En el caso de los varones, antecedentes de síntomas de obstrucción miccional, p. ej. retención urinaria. o En el caso de las mujeres: - embarazo, lactancia materna o posibilidad de concebir durante el estudio; - si son fértiles, no utilizar un método anticonceptivo eficaz (esterilización quirúrgica, anticonceptivos hormonales o dispositivo intrauterino); - positivo en la prueba del embarazo de la beta-hCG en suero en la selección. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy end-point is the primary criterion will be the response rate defined as the percentage of patients with a Modified Rankin Scale (mRS) less than or equal to 2 at Week 12. |
El criterio principal de valoración será la tasa de respuesta, definida como el porcentaje de pacientes con una puntuación menor o igual a 2 en la Escala de Rankin modificada (mRS) en la semana 12. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficay end point will be measure at Week 12 |
El criterio principal de valoración será medido en la Semana 12. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy criteria include: 1) The change from baseline to Week 12 of the: - mRS score, - mean NIHSS total and motor scores, 2) The percentage of patients with : - an NIHSS score less than or equal to 5 at Week 12, - at least one moderate to severe depressive episode (MADRS > 25 and or CGI-depression > 4) at Week 12.
Safety end-points: 1) percentage of patients reporting at least one adverse event (AE) in each group, 2) physical examination, vital sign measurements 3) electrocardiograms (ECGs), 4) clinical laboratory values. |
Los Criterios secundarios de valoración de la eficacia incluyen: 1) Variación en la semana 12, respecto al valor basal, de: - la puntuación de la mRS; - la puntuación media total y la puntuación motriz de la NIHSS. 2) Porcentaje de pacientes con: - puntuación menor o igual a 5 en la NIHSS a la semana 12; - al menos un episodio depresivo moderado o grave (MADRS > 25 o CGI-depresión > 4) a la semana 12.
Criterios de Seguridad: 1) Porcentaje de pacientes que refieren al menos un acontecimiento adverso (AA) en cada grupo. 2) Datos de las exploraciones físicas y constantes vitales. 3) Electrocardiogramas (ECG). 4) Análisis clínicos de laboratorio. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary efficacy endpoints will be measured at Week 12.
The safety end points will be measured at each visit |
Los Criterios secundarios de valoración de la eficacia se medirán en la Semana 12.
Los Criterios de seguridad se medirán en cada visita. |
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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 | 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 | 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 | 2 |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 72 |
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 |
Belgium |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Italy |
Netherlands |
Portugal |
Russian Federation |
Spain |
Sweden |
Switzerland |
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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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Last visit of last patient as per protocol |
Última visita del último paciente, según el protocolo. |
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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 | 10 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |