E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adrenomyeloneuropathy |
Adrenomieloneuropatia (AMN) |
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E.1.1.1 | Medical condition in easily understood language |
Adrenomyeloneuropathy |
Adrenomieloneuropatia (AMN) |
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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 | LLT |
E.1.2 | Classification code | 10069075 |
E.1.2 | Term | Adrenomyeloneuropathy without cerebral involvement |
E.1.2 | System Organ Class | 100000004850 |
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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 goal of the trial is to show that treatment with plasma exchange plus therapeutic albumin replacement in patients with AMN induces a decrease of plasma and cerebrospinal fluid VLCFA. |
El objetivo principal del ensayo es demostrar que el tratamiento con plasmaféresis más el reemplazo terapéutico de albúmina en pacientes con AMN induce una disminución de los VLCFA del plasma y del líquido cefalorraquídeo. |
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E.2.2 | Secondary objectives of the trial |
The secondary goal of the trial is the assessment of efficacy and safety of the proposed treatment in 5 patients with AMN. Efficacy will be measured in terms of motor function and quality of life. Only in case of a decrease in VLCFA other biological markers (oxidation and inflammation biomarkers) will also be studied. Safety will be evaluated by clinical and biochemical exams and recording of any adverse event. |
El objetivo secundario del ensayo es la valoración de la eficacia y seguridad del tratamiento propuesto en 5 pacientes con AMN. Mediremos la eficacia en términos de función motora y calidad de vida. Estudiaremos también otros marcadores biológicos (marcadores de oxidación e inflamación) únicamente en el caso de una disminución de los VLCFA. Evaluaremos la seguridad con exámenes clínicos y bioquímicos y registraremos los efectos secundarios |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men of 18 to 65 years old, inclusive 2. Elevated plasma VLCFA and gene mutation identified 3. Clinical signs of AMN with at least pyramidal signs in the lower limbs and difficulties to run 4. Presence of motor deficit according to the EDSS scale 5. Ability to perform the 2MWT 6. Normal brain MRI or brain MRI showing the following abnormalities that can be observed in AMN patients without cerebral form of X‐ALD, obtained in the 6 months prior to screening: •abnormal hyperintensity of pyramidal tract fibers in the brain stem on FLAIR or T2 sequence •abnormal hyperintensity of pyramidal tract fibers in the internal capsules on FLAIR or T2 sequence •cerebellar atrophy •moderate cortical atrophy 7. Appropriate steroid replacement if adrenal insufficiency is present 8. Signed Informed consent 9. Affiliated to the Spanish Public Health System |
1. Varones de 18 a 65 años, ambos incluidos 2. VLCFA elevados en plasma e identificada la mutación en el gen. 3. Signos clínicos de AMN con signos piramidales en las extremidades inferiores y dificultades para correr como mínimo 4. Presencia de déficit motor según escala EDSS 5. Aptitud para realizar el test 2MWT 6. RMN cerebral normal o RMN cerebral con las siguientes anormalidades que pueden observarse en pacientes sin la forma cerebral de AMN, obtenida durante los 6 meses anteriores a la visita de selección: - hiperintensidad anormal de las fibras de los tractos piramidales en el tronco cerebral en secuencias FLAIR o T2 - atrofia cerebelar - atrofia cortical moderada 7. Reemplazo de esteroides adecuado en caso de insuficiencia adrenal 8. Consentimiento informado firmado 9. Afiliado al Sistema de Salud Público Español |
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E.4 | Principal exclusion criteria |
1. Any contraindication for plasma exchange due to behavioral disorders or abnormal coagulation parameters, such for example: - Hypocalcemia (Ca++ < 8.7 mg/dl) - Thrombocytopenia (< 100.000/µl) - Fibrinogen < 1.5 g/l - Prothrombin time (Quick) p< 60% versus control (INR > 1.5) - Beta-blocker treatment and bradycardia < 55/min - Treatment with ACIs (increased risk of allergic reactions) 2. Hemoglobin < 10 g/dl 3. Difficult venous access precluding plasma exchange 4. A history of frequent adverse reactions (serious or otherwise) to blood products 5. Hipersensibility to albumin o allergies to any of the components of Albunorm® 5% 6. Plasma creatine > 2 mg/dl 7. Uncontrolled high blood pressure (systolic blood pressure of 160 mmHg or higher and/or diastolic blood pressure of 100 mmHg or higher despite regular treatment during the last 3 months) 8. Liver cirrhosis or any liver problem with GPT > 2.5 x ULN, or bilirubin > 2 mg/dl 9. Heart diseases as evidenced by myocardial infarction, severe or unstable angina, or heart failure in the past 12 months 10. Gadolinium enhancement on T1 sequence of any abnormal hypersignal of white matter, including myelinated pyramidal tracts, visible at brain MRI on FLAIR sequences 11. Significant peripheral edema (2+ or more on the Assessment Chart for Pitting Edema) of the extremities of any etiology 12. Any evolutive malignancy during the last five years or any condition complicating adherence to the study protocol 13. Smokers (one pack/ day or more for at least 20 years), current or former 14. Any psychiatric disease 15. Present participation to another therapeutic clinical trial for X-ALD, or the receipt of any other investigational drug in the three months prior to the start of the study 16. Patients being treated with anticoagulants or antiplatelet therapy 17. Not easily contactable by the investigator in case of emergency or not capable to call the investigator |
1. Cualquier contraindicación para el recambio plasmático debido a trastornos del comportamiento o parámetros de coagulación anormales, tales como: - Hipocalcemia (Ca++ < 8.7 mg/dl) - Trombocitopenia (< 100.000/μl) - Fibrinógeno < 1.5 g/l - Tiempo de protrombina (Quick) p<60% versus control (INR) > 1.5) - Tratamiento con beta-bloqueantes y bradicardia < 55/min - Tratamiento con ACIs (riesgo aumentado de reacciones alérgicas) 2. Hemoglobina < 10 g/dl 3. Dificultad de acceso a las venas que impida el recambio plasmático 4. Historial de reacciones adversas frecuentes (serias o de otro tipo) 5. Hipersensibilidad a la albúmina o alergias a alguno de los componentes de Albunorm® 5% 6. Creatina plasmática > 2 mg/dl 7. Presión sanguínea alta no controlada (presión sistólica de 160 mmHg o superior y/o presión diastólica de 100 mmHg o superior, a pesar de tratamiento regular durante los últimos 3 meses) 8. Cirrosis hepática o algun problema hepático con GPT > 2.5 x ULN o bilirrubina > 2 mg/dl 9. Enfermedades cardíacas tales como infarto de miocardio severo o angina de pecho inestable, o insuficiencia cardíaca en los últimos 12 meses 10. Captación de gadolinio en secuencia T1 de cualquier hiperseñal anormal de sustancia blanca, incluyendo tractos piramidales mielinizados, visible en RMN cerebral en secuencias FLAIR 11. Edema periférico significativo (2+ o más en el modelo de evaluación para el edema con fóvea) de las extremidades de cualquier etiología 12. Alguna neoplasia evolutiva durante los últimos 5 años o cualquier otro trastorno que complique el cumplimiento del protocolo del estudio 13. Fumadores (un paquete/día o más durante los últimos 20 años), actual o anterior 14. Alguna enfermedad psiquiátrica 15. Estar participando en otro ensayo clínico para pacientes X-ALD, o haber recibido cualquier otro fármaco en investigación durante los tres meses anteriores al inicio del estudio 16. Pacientes que estén siendo tratados con anticoagulantes o antiplaquetarios 17. Sujeto no fácilmente localizable por el investigador en caso de emergencia o incapaz de llamar al investigador. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The main efficacy evaluation criterion is changes in plasma VLCFA between M0 and M6. C26:0, C24:0 and C26:0/C22:0 will be measured in plasma. |
El principal criterio de evaluación de la eficacia son cambios en los VLCFA plasmáticos entre M0 y M6. Mediremos C26:0, C24:0 y 26:0/C22:0 en plasma. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The assessment of the main variable is in month 6. |
La valoración de la variable principal es al mes 6. |
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E.5.2 | Secondary end point(s) |
Efficacy endpoints:
1) Tests evaluating the motor functions of treated AMN patients. They include: the Timed Up and Go (TUG) test, the Time to walk 25 feet (TW25), the 2 minute walk test (2MWT) and the 6 minute walk test (6MWT) on M0, M6 and M12. 2) Quality of life: score of SF-Qualiveen on M0, M6 and M12. 3) VLCFA in CSF (optional): C26:0, C24:0 and C26:0/C22:0 will be measured in CSF in those patients with AMN who voluntarily accept to undergo a lumbar puncture on M0, M6 and M12. 4) Biological measures (only in case of a decrease in VLCFA): - Marker of oxidative stress: 8oxo-dG in urine. 8oxo-dG will be measured on M0, M6 and M12. - Markers of inflammation: CCR3, CXCL5, CXCL9, IL9R, PPARd, GPX4 and STAT1 in RNA obtained from MNC and HGF, IL6, IL8, MCP-1, NGF, TNF and adiponectin in plasma will be measured on M0, M6 and M12.
Safety endpoints:
Safety will be evaluated by clinical and biochemical exams and recording of any adverse event. |
Variables de eficacia:
1) Tests de evaluación de las funciones motoras de los pacientes AMN tratados. Incluyen: prueba cronometrada de "levántate y anda" (TUG), tiempo empleado para caminar 25 pies (TW25), prueba de caminata de 2 minutos (2MWT) y prueba de caminata de 6 minutos (6MWT) a M0, M6 y M12 2) Calidad de vida: puntuación SF-Qualiveen a M0, M6 y M12 3) VLCFA en LCR (opcional): mediremos C26:0, C24:0 and C26:0/C22:0 en LCR en aquellos pacientesAMN que acepten voluntariamente someterse a una punción lumbar en M0, M6 y M12 4) Medidas biológicas: (sólo en el caso de disminución de VLCFA): - Marcadores de estrés oxidativo: 8oxo-dG en orina. Mediremos 8oxo-dG a M0, M6 y M12 - Marcadores de inflamación: CCR3, CXCL5, CXCL9, IL9R, PPARd, GPX4 y STAT1 en RNA obtenido a partir de MNC y HGF, IL6, IL8, MCP-1, NGF, TNF y adiponectina en plasma a M0, M6 y M12
Variables de seguridad:
Evaluaremos la seguridad mediante exámenes clínicos y bioquímicos y registraremos los acontecimientos adversos |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The assessment of the secondary endpoints are in month 0, 6 i 12 (M0, M6, M12) |
La valoración de las variables secundarias son al mes 0, 6 i 12 (M0, M6, M12) |
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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 | 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.8.3 |
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 | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 last subject |
Último paciente última visita |
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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 | |
E.8.9.1 | In the Member State concerned months | 13 |
E.8.9.1 | In the Member State concerned days | |