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 |
Amyotrophic Lateral Sclerosis is a type of Motor Neurone Disease. It is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. |
ELA es un tipo de enfermedad neuronal motora. Es una enfermedad progresiva del SN que afecta a las células nerviosas del cerebro y la médula espinal, provocando la pérdida de control muscular. |
|
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 | 21.1 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of PTC857 in reducing disease progression in subjects with ALS. |
Evaluar la eficacia de PTC857 para reducir la progresión de la enfermedad en pacientes con esclerosis lateral amiotrófica (ELA). |
|
E.2.2 | Secondary objectives of the trial |
Secondary Objectives: 1. Safety and tolerability of PTC857 in subjects with ALS 2. Respiratory function in subjects randomized to PTC857 versus placebo 3. Motor/limb and bulbar function in subjects randomized to PTC857 versus placebo 4. Neuropsychological function in subjects randomized to PTC857 versus placebo 5. Survival in subjects randomized to PTC857 versus placebo 6. Quality of life in subjects randomized to PTC857 versus placebo 7. Pharmacokinetics of PTC857
Exploratory Objective: Effects on biomarker activity in subjects randomized to PTC857 versus placebo
Long-Term Extension Period Objectives: 1. Disease progression, survival, neuropsychological function, respiratory function, motor/limb and bulbar function, and effects on biomarker activity upon long-term treatment with PTC857 2. Safety and tolerability upon long-term treatment with PTC857 3. Quality of life upon long-term treatment with PTC857 4. PK of PTC857 |
Objetivos secundarios
1. La seguridad y tolerabilidad de PTC857. 2. La función respiratoria de los/as pacientes aleatorizados a recibir PTC857 frente a un placebo. 3. La función motora/de las extremidades y bulbar en pacientes aleatorizados a recibir PTC857 frente a un placebo. 4. La función neuropsicológica en pacientes aleatorizados a recibir PTC857 frente a un placebo. 5. La supervivencia en pacientes aleatorizados a recibir PTC857 frente a un placebo. 6. La calidad de vida en pacientes aleatorizados a recibir PTC857 frente a un placebo. 7. La farmacocinética (FC) de PTC857. |
|
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 |
Pharmacokinetics sub-study |
Subestudio de análisis de la farmacocinética |
|
E.3 | Principal inclusion criteria |
1. Males or females aged between 18 and 70 years with a body mass index (BMI) between 18 and 35 kg/m2
2. ALS with preserved function, defined as: a. Onset of the first symptom leading to the diagnosis of ALS ≥7 and ≤18 months at the time of the initial Screening Visit b. Revised EL Escorial criteria of either: (i) Clinically definite ALS (ii) Clinically probable ALS
3. A total ALSFRS-R score of at least 34 at the start of the Screening Period
4. No significant respiratory compromise as evidenced by slow vital capacity ≥60%
5. All concomitant medications (both prescription and over the counter [OTC]) and non pharmacologic therapy regimens should be stable and unchanged from 30 days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study, with the exception of prohibited medications |
1. Hombres o mujeres de entre 18 y 70 años que tengan un índice de masa corporal (IMC) de entre 18 y 35 kg/m2.
2. Diagnóstico de ELA con funcionalidad mantenida, definida como: a. Aparición del primer síntoma que resultase en el diagnóstico de ELA ≥7 o ≤18 meses antes de la visita de selección inicial. b. Criterios revisados de El Escorial para el diagnóstico del ELA de: (i) ELA definitivo desde un punto de vista clínico (ii) ELA probable desde un punto de vista clínico
3. Una puntuación total en la escala ALSFRS-R de al menos 34 al inicio del período de selección.
4. Ausencia de un compromiso respiratorio importante, según lo demostrado por una capacidad vital lenta ≥60 % en una espirometría.
5. Todos los medicamentos concomitantes (tanto sujetos a receta médica como los de venta sin receta) y las pautas de tratamiento no farmacológicas deben haberse mantenido estables y sin cambios a partir de los 30 días anteriores al inicio del período de selección y prever mantenerse estables y sin cambios durante el desarrollo del estudio, a excepción de los medicamentos no autorizados |
|
E.4 | Principal exclusion criteria |
1. Females who are pregnant or nursing or plan to become pregnant during the study 2. Subjects with clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular/ischemic disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the subject or impact the validity of the study results 3. Any clinically significant medical or psychiatric condition or medical history that, in the opinion of the investigator or the medical monitor, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject 4. Current participation in any other investigational study with an investigational product or participation within 30 days prior to the start of the Screening Period or 5 half-lives of the previously taken investigational drug, whichever is longer 5. Subject has previously received PTC857 6. Edaravone treatment, where applicable, within 30 days prior to the start of the Screening Period |
1. Mujeres embarazadas, en período de lactancia o que planean quedarse embarazadas durante el transcurso del estudio 2. Pacientes con una enfermedad gastrointestinal, renal, hepática, neurológica, hematológica, endocrina, oncológica, pulmonar, inmunitaria, psiquiátrica o cardiovascular/isquémica de trascendencia clínica o con cualquier otra afección que, a criterio del/de la investigador/a, podría poner en peligro la seguridad del/de la paciente o afectar a la validez de los resultados del estudio. 3. Cualquier afección médica o psiquiátrica de trascendencia clínica o cualquier antecedente médico que, en opinión del/de la investigador/a o del monitor médico, podría interferir con la capacidad del/de la paciente para participar en el estudio o aumentar el riesgo de la participación de dicho/a paciente. 4. Participación actual en cualquier otro estudio de investigación en el que se utilice un producto en investigación o participación en un estudio de este tipo en los 30 días anteriores al inicio del período de selección o las 5 semividas del fármaco experimental tomado previamente, según el que corresponda al período más extenso. 5. Antecedentes de tratamiento previo con PTC857. 6. Tratamiento con edaravona, cuando proceda, en los 30 días anteriores al inicio del período de selección. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) in the modified Intent-to-Treat Analysis Set (mITT) after 24 weeks of treatment |
Cambio con respecto al inicio del estudio en la escala revisada de valoración funcional en la esclerosis lateral amiotrófica (ALSFRS‑R, ALS Functional Rating Scale-Revised) en el conjunto de análisis por intención de tratar modificada (IDTm) tras 24 semanas de tratamiento. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Secondary Endpoints: 1. Change from baseline in ALSFRS-R in the Intent-to-Treat (ITT) Analysis Set after 24 weeks of treatment 2. Safety and tolerability of PTC857 as measured by the severity and number of TEAEs and TESAEs, and change in clinical laboratory tests, physical examination, vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS), and 12-lead electrocardiograms (ECGs) during the Treatment Period 3. Change from baseline in respiratory function as assessed by pulmonary function tests (PFTs) after 24 weeks of treatment 4. Change from baseline in motor/limb and bulbar function as assessed by the Modified Norris Scale after 24 weeks of treatment 5. Change from baseline in neuropsychological function as assessed by the ALS Cognitive Behavioral Screen (ALS CBS) after 24 weeks of treatment 6. Survival as assessed by rate of and length of time to needing respiratory support/intubation and/or death 7. Survival and functional change as assessed by the Combined Assessment of Function and Survival (CAFS) after 24 weeks of treatment 8. Quality of life as assessed by Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) after 24 weeks of treatment 9. Plasma PK and cerebrospinal fluid (CSF) exposure of PTC857
Exploratory Endpoint: Change from baseline in blood, urine, and CSF biomarker activity after 24 weeks of treatment
Long-Term Extension Endpoints: 1. Severity and number of TEAEs and TESAEs, change in clinical laboratory tests, physical examination, vital signs, and 12-lead ECGs during the long-term treatment 2. Change from baseline in ALSFRS-R with long-term treatment 3. Change from baseline in respiratory function as assessed by PFTs with long-term treatment 4. Change from baseline in motor/limb and bulbar function as assessed by the Modified Norris Scale with long-term treatment 5. Change from baseline in neuropsychological function as assessed by the ALS CBS with long-term treatment 6. Survival and functional change as assessed by CAFS with long-term treatment 7. Time to needing respiratory support/intubation and/or death with long-term treatment 8. Quality of life as assessed by ALSAQ-40 with long-term treatment 9. Change from baseline in blood and urine biomarker activity with long-term treatment 10. PK of PTC857 |
Criterios de valoración secundarios
1. El cambio con respecto al inicio del estudio en la escala ALSFRS-R en el análisis por intención de tratar (IDT) tras 24 semanas de tratamiento. 2. La seguridad y tolerabilidad de PTC857, determinadas en función de la gravedad y el número de acontecimientos adversos surgidos durante el tratamiento (AAST) y de acontecimientos adversos graves surgidos durante el tratamiento (AAGST) 3. El cambio con respecto al inicio del estudio en la función respiratoria, según lo determinado mediante pruebas de la función pulmonar (PFP) realizadas tras 24 semanas de tratamiento. 4. El cambio con respecto al inicio del estudio en la función motora/de las extremidades y bulbar, según lo determinado mediante la escala modificada de Norris tras 24 semanas de tratamiento. 5. El cambio con respecto al inicio del estudio en la función neuropsicológica, según lo determinado mediante la prueba de cribado cognitivo conductual en la ELA (ALS‑CBS, ALS Cognitive Behavioral Screen) tras 24 semanas de tratamiento. 6. La supervivencia, evaluada en función de la tasa de requerimiento de ventilación mecánica/intubación o muerte, así como el tiempo transcurrido hasta alguno de estos eventos. 7. La supervivencia y el cambio en la funcionalidad, determinados mediante la evaluación combinada de la funcionalidad y la supervivencia (CAFS, Combined Assessment of Function and Survival) tras 24 semanas de tratamiento. 8. La calidad de vida, evaluada mediante el cuestionario de evaluación de la esclerosis lateral amiotrófica de 40 preguntas (ALSAQ‑40, Amyotrophic Lateral Sclerosis Assessment Questionnaire) tras 24 semanas de tratamiento. 9. La FC plasmática y la exposición del líquido cefalorraquídeo (LCR) a PTC857. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary and Exploratory Endpoints: 24 weeks Long-Term Extension Period Endpoints: 52 weeks |
Criterios de valoración secundarios y exploratorios: 24 semanas Criterios de valoración del período de extensión a largo plazo: 52 semanas |
|
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 | 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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
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 |
Argentina |
Australia |
Brazil |
Japan |
Mexico |
United States |
France |
Poland |
Sweden |
Netherlands |
Spain |
Czechia |
Germany |
Italy |
Belgium |
|
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 - A subject is considered to have completed the study if she/he has completed all Part B study visits (or Part A if they are not participating in the optional LTE Period), including the follow-up telephone call. |
UVUP - Se considera que un sujeto ha completado el estudio si ha finalizado todas las visitas del estudio de la Parte B (o de la Parte A si no participa en el Periodo ELP opcional), incluida la llamada telefónica de seguimiento. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |