E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS) |
Esclerosis lateral amiotrófica (ELA). |
|
E.1.1.1 | Medical condition in easily understood language |
ALS is a disorder that affects the function of nerves and muscles, eventually taking away the ability to walk, dress, write speak, swallow, and breathe and shortening the life span |
ELA es un desorden que afecta la función de nervios y músculos, eventualmente afectando la capacidad de caminar, vestirse, escribir hablar, tragar, y respirar y acortar la vida útil |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002026 |
E.1.2 | Term | Amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective, in addition to continuing treatment for subjects in this study, is to evaluate long-term safety of oral levosimendan in amyotrophic lateral sclerosis (ALS) patients. |
El objetivo principal de este estudio, además de continuar el tratamiento de los sujetos del estudio REFALS, es evaluar la seguridad a largo plazo de levosimendán oral en pacientes con esclerosis lateral amiotrófica (ELA). |
|
E.2.2 | Secondary objectives of the trial |
The secondary objective is to explore long-term effectiveness of oral levosimendan in the treatment of patients with ALS, by continuing to observe rate of disease progression during the treatment. |
El objetivo secundario de este estudio es explorar la eficacia a largo plazo de levosimendán oral en el tratamiento de pacientes con ELA mediante el seguimiento de la tasa de progresión de la enfermedad durante el tratamiento. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be included into the study: 1.Written or verbal informed consent (IC) for participation in the study will be obtained from the subject. In case that the study subject him/herself cannot sign the IC, a witness may sign the consent form to indicate that the subject has given verbal consent. 2. Subjects who completed 48 weeks of treatment according to the REFALS study protocol. 3. Able to swallow study treatment capsules at the time of completing 48 weeks dosing in the REFALS study |
Los sujetos deben cumplir todos los criterios siguientes para participar en el estudio: 1.Proporcionar su consentimiento informado (CI), verbal o por escrito. En caso de que el sujeto del estudio no pueda firmar el CI por sí solo, un testigo puede firmar el formulario de consentimiento para indicar que el sujeto ha otorgado el consentimiento verbal. 2.Haber completado 48 semanas de tratamiento de acuerdo con el protocolo del estudio REFALS. 3.Ser capaz de tragar las cápsulas de tratamiento del estudio al finalizar las 48 semanas de tratamiento en el estudio REFALS. |
|
E.4 | Principal exclusion criteria |
Subjects will not be included into this study if they meet any of the following criteria: 1. Development (or significant worsening from baseline of the REFALS study) of serious cardiovascular disease (e.g. myocardial infarction, heart failure, arrhythmia, stroke, or second or third degree atrioventricular (AV) block). 2. Pulse/heart rate repeatedly > 100 bpm after 5-minute rest at baseline. If the pulse/heart rate is > 100 bpm in the first recording, then a second recording must be done after another 5 min rest to confirm pulse/heart rate > 100 bpm. 3. Systolic blood pressure (SBP) < 90 mmHg. 4. Severe renal impairment (creatinine clearance < 30 ml/min or creatinine > 170 µmol/l at 48 week visit of the REFALS study, or on dialysis. 5. Severe hepatic impairment at the discretion of the investigator. 6. Women of reproductive age without a negative pregnancy test and without a commitment to using a highly effective method of contraception (e.g. oral hormonal contraceptives associated with inhibition of ovulation, intrauterine devices and long acting progestin agents), if sexually active during the study, and for 1 month after the last dose of the study treatment. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be reproductive and can be included. 7. Subject judged to be actively suicidal by the investigator. 8. Any other clinically significant cardiovascular, gastrointestinal, hepatic, renal, neurological or psychiatric disorder or any other major concurrent illness that in the opinion of the investigator could interfere with the interpretation of the study results or constitute a health risk for the subject if he/she took part in the study. |
Los sujetos que cumplan alguno de los siguientes criterios no podrán participar en este estudio: 1.Desarrollo (o empeoramiento considerable respecto del inicio del estudio REFALS) de una enfermedad cardiovascular grave (p. ej., infarto del miocardio, fallo cardiaco, arritmia, derrame cerebral o bloqueo auriculoventricular [AV] de segundo o tercer grado). 2.Pulso/frecuencia cardiaca >100 lpm de forma reiterada después de 5 minutos de reposo al inicio. Si el pulso o frecuencia cardiaca es >100 lpm en el primer registro, debe realizarse un segundo registro después de otros 5 minutos de reposo para confirmar si sigue siendo >100 lpm. 3.Presión arterial sistólica (PAS) <90 mmHg. 4.Alteración renal grave (aclaramiento de creatinina <30 ml/min o creatinina >170 µmol/l en la visita de la semana 48 del estudio REFALS, o en diálisis). 5.Deterioro hepático grave a criterio del investigador. 6.Mujeres en edad fértil sin una prueba de embarazo negativa y que no se comprometan a utilizar un método anticonceptivo de alta eficacia (p. ej., anticonceptivos hormonales orales asociados con la inhibición de la ovulación, dispositivos intrauterinos y agentes de progestina de acción prolongada), si son sexualmente activas durante el estudio y durante 1 mes después de la última dosis de tratamiento del estudio. Las mujeres posmenopáusicas (1 año desde su último ciclo menstrual), esterilizadas quirúrgicamente o que se hayan sometido a una histerectomía, se consideran no fértiles y pueden ser incluidas. 7.Sujetos que, según el criterio del investigador, tienen ideación suicida activa. 8.Cualquier otro trastorno cardiovascular, gastrointestinal, hepático, renal, neurológico o psiquiátrico de importancia clínica, o cualquier otra enfermedad simultánea importante que, a criterio del investigador, podría interferir en la interpretación de los resultados del estudio o suponer un riesgo para la salud del sujeto si este participase en el estudio. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
This study is not endpoint driven. The primary and secondary objectives are summarized below. Safety will be assessed by adverse events (AEs), vital signs, 12-lead electrocardiogram (ECG) and by assessment of suicidality. |
Este estudio no se conduce por objetivos finales. A continuación se resumen los objetivos primarios y secundarios. La seguridad se evaluará mediante el registro de acontecimientos adversos (AA), constantes vitales, electrocardiogramas (ECG) de 12 derivaciones y evaluación de tendencias suicidas. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis will take place at end of the study, and be summarized with and without data from REFALS 3119002 study. |
El análisis se llevará a cabo al final del estudio, y se resumirá con y sin datos del estudio REFALS 3119002. |
|
E.5.2 | Secondary end point(s) |
Secondary objectives is efficacy and include: Slope of decline in sitting and supine SVC and ALSFRS-R will be estimated using a random slope model. Median time to non-invasive mask ventilation (NIV) or death and to decline (by at least 1 point) in the ALSFRS-R respiratory domain will be evaluated using Kaplan-Meier estimates. Borg CR10 (sitting, supine and orthostatic changes) will be evaluated using mixed model for repeated measures. Health and home care resource use data will be summarized in the study report, but any further analysis for potential pharmacoeconomic purposes will be reported separately. |
Los objetivos secundarios son la eficacia e incluyen: Se estimará la pendiente de declive de la SVC y la escala ALSFRS-R en posición sentada y en supino mediante un modelo de pendiente aleatoria. Se evaluará el tiempo mediano hasta la ventilación no invasiva (VNI) con mascarilla o la muerte y hasta la disminución (de al menos 1 punto) en la función respiratoria de la escala ALSFRS-R mediante estimaciones de Kaplan-Meier. Se evaluará la escala CR-10 de Borg (en posición sentada, en supino y cambios ortostáticos) mediante un modelo de efectos mixtos para medidas repetidas. Los datos de consumo de recursos asistenciales y de atención domiciliaria se resumirán en el informe del estudio, pero los análisis adicionales para propósitos farmacoeconómicos se presentarán en otro informe. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis will take place at end of the study, and be summarized with and without data from REFALS 3119002 study. |
El análisis se llevará a cabo al final del estudio, y se resumirá con y sin datos del estudio REFALS 3119002. |
|
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 | 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 | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | 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 | 1 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 43 |
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 |
Belgium |
Canada |
Finland |
France |
Germany |
Ireland |
Italy |
Netherlands |
Spain |
Sweden |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS |
Última visita del ultimo sujeto |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |