E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Painful Diabetic Neuropathy |
Neuropatía diabética dolorosa |
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E.1.1.1 | Medical condition in easily understood language |
Painful Diabetic Neuropathy (complication of diabetes) |
Neuropatía diabética dolorosa (complicación de diabetes) |
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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 | 10067547 |
E.1.2 | Term | Diabetic peripheral neuropathic pain |
E.1.2 | System Organ Class | 100000004852 |
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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 compare the efficacy of EMA401 vs. placebo in 24-hour average pain intensity score at Week 12, using an 11 point Numeric Rating Scale (NRS) by testing the superiority of EMA401 vs. placebo |
Comparar la eficacia de EMA401 vs. placebo en el promedio de puntuación de la intensidad del dolor a las 24 horas en la Semana 12, utilizando una escala de puntuación numérica (NRS) de 11 puntos, comprobando la superioridad de EMA401 100 mg b.i.d vs. placebo |
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E.2.2 | Secondary objectives of the trial |
•Compare the efficacy of EMA401 vs placebo in NPSI total score by testing the superiority of EMA401 vs placebo •Evaluate the efficacy of EMA401 compared to placebo, as measured by the BPI-SF total score at Wk 12; as measured by the weekly mean of the 24-hour worst pain intensity score, using the NRS at Wk 12; on the PGIC at Wk 12 •Evaluate the proportion of EMA401 patients achieving a ≥ 30% and a ≥ 50% reduction in weekly mean 24-hr average pain intensity score using the NRS vs placebo at Wk 12 •Evaluate the effect of EMA401 vs placebo on the ISI at Wk 12 •Evaluate the safety and tolerability of EMA401 vs placebo, as measured by treatment-emergent AEs, AEs leading to study drug discontinuation and SAEs •Evaluate the PK of EMA401 and exposure-response relationship for EMA401 •Evaluate the proportion of patients who need rescue medication separately for the treatment epoch and treatment withdrawal epoch and the time to first intake of rescue medication during the treatment epoch |
Evaluar: -la eficacia de EMA401 vs placebo (PL), por la puntuación total de NPSI . -la eficacia de EMA401 vs PL, medida por la media semanal de la puntuación de la intensidad del peor dolor tras 24 hrs, utilizando NRS de 11 ptos en la Semana 12 (Wk 12) y por la PGIC (Wk 12) - la proporción de pacientes tratados con EMA401 que alcancen una reducción >/=30% y una reducción >/=50% en la media semanal del promedio de puntuación de intensidad del dolor a las 24 hrs utilizando la NRS en la Wk 12 -el efecto de EMA401 vs PL utilizando el ISI en la Wk 12 -la seguridad y tolerabilidad de EMA401 vs PL en pacientes con NDD, medidas por los AAET, los AAs que den lugar a la interrupción del tto. y los AAGs . - PK y la relación exposición-respuesta para EMA401. - la proporción de pacientes que necesiten tto. rescate para la fase de tto. doble ciego y la fase de retirada del tto. y el tiempo hasta la toma el tto. de rescate durante la fase de doble ciego. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• At the time of Screening, have documented diagnosis of Type I OR Type II diabetes mellitus (DM) with painful distal symmetrical sensorimotor neuropathy (for example ICD-10 code G63.2) of more than 6 months duration with any one or more of the following: - Neuropathic symptoms (e.g. numbness, non-painful paresthesias or tingling, non-painful sensory distortions or misinterpretations, etc.) - Decreased distal sensation (e.g. decreased vibration, pinprick sensation, light touch, etc.) • Be assessed as suffering from moderate to severe neuropathic pain across the Screening epoch. • A score of ≥ 4 on the Douleur Neuropathique en 4 Questions (DN4) questionnaire at Screening.
Other protocol-defined inclusion criteria may apply. |
En el momento de la Selección, tener documentado un diagnóstico de diabetes mellitus (DM) Tipo I o Tipo II con neuropatía sensorimotora simétrica distal dolorosa (por ejemplo ICD-10 código G63.2) de más de 6 meses de duración con uno o más de los siguientes: -Síntomas neuropáticos (p. ej., entumecimiento, parestesias no dolorosas u hormigueo, distorsiones sensoriales no dolorosas o malas interpretaciones, etc.) -Sensación distal reducida (p. ej., vibración reducida, sensación de pinchazos, toques leves, etc.) -Ser evaluado como padecer un dolor neuropático moderado a intenso durante la fase de selección -Una puntuación de >/=4 en el cuestionario de Dolor neuropático en 4 Preguntas (DN4) en la selección Otros criterios de inclusión definidos en el protocolo también pueden proceder. |
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E.4 | Principal exclusion criteria |
• History or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study. • Major depressive episode within 6 months prior to Screening and/or a history of diagnosed recurrent major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) diagnostic criteria. • Have evidence of significant renal insufficiency or pre-existing liver condition. • Have platelets ≤ 100 x 109/L, or neutrophil count < 1.2 x 109/L (or equivalent), hemoglobin ≤ 100 g/L for women or hemoglobin ≤ 110 g/L for men. • Participants whose glycemic control has been unstable within 3 months immediately prior to screening (e.g., ketoacidosis requiring hospitalization, any recent episode of hypoglycemia requiring assistance through medical intervention, uncontrolled hyperglycemia). • Patients with any differential diagnosis of PDN including but not limited to other neuropathies (e.g. Vitamin B12 deficiency, Chronic Inflammatory Demyelinating Polyneuropathy), polyradiculopathies, central disorders (e.g. demyelinating disease), or rheumatological disease (e.g., foot arthritis, plantar fasciitis). • Patient is unwilling or unable to complete daily eDiary.
Other protocol-defined exclusion criteria may apply. |
-Antecedentes o diagnóstico actual de anormalidades en el electrocardiograma (ECG) que indiquen un riesgo significativo de seguridad para los pacientes que participen en el estudio -Episodio depresivo mayor en un período de 6 meses antes de la Selección y/o antecedentes de trastorno depresivo mayor recurrente diagnosticado de acuerdo con los criterios diagnósticos del Manual Diagnóstico y Estadístico de Trastornos Mentales, 5ª Edición (DSM-V) -Tener evidencia de insuficiencia renal significativa o hepatopatía preexistente -Tener un número de plaquetas </=100 x 109/L, o de neutrófilos <1,2 x 109/L (o equivalente), hemoglobina </= 100 g/L para mujeres o hemoglobina </= 110 g/L para hombres -Participantes cuyo control glucémico haya sido inestable en los 3 meses inmediatamente anteriores a la selección (p. ej., cetoacidosis que requiera hospitalización, cualquier episodio reciente de hipoglucemia que requiera asistencia mediante intervención médica, hiperglucemia no controlada) - Pacientes con cualquier diagnóstico diferencial de NDD incluidas pero no limitadas a otras neuropatías (p. ej., deficiencia de vitamina B12, polineuropatía desmielinizante inflamatoria crónica), poliradiculopatías, trastornos centrales (p. ej., enfermedad desmielinizante), o enfermedad reumatológica (p. ej., artritis en los pies, fascitis plantar) - Pacientes que no estén dispuestos o no puedan completar diariamente el Diario electrónico |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in weekly mean 24-hour average pain score (using the 11 point NRS) from Baseline to Week 12 |
Medida por la media semanal de la intensidad del dolor a las 24 horas en la Semana 12, utilizando una escala de puntuación numérica (NRS) de 11 puntos |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline, Week 12 |
Selección, Semana 12 |
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E.5.2 | Secondary end point(s) |
• Change in Neuropathic Pain Symptom Inventory (NPSI) total score from Baseline to Week 12 • Change in Brief Pain Inventory-Short Form (BPI-SF) interference total score from Baseline to Week 12 • Change in weekly mean of the 24-hour worst pain score, using an 11-point Numeric Rating Scale (NRS), from Baseline to Week 12 • Patient Global Impression of Change (PGIC) at Week 12 • Proportion of patients meeting responder criteria from Baseline to Week 12 • Change in Insomnia Severity Index (ISI) from Baseline to Week 12 • Number and severity of treatment- emergent adverse events and the frequency of adverse events leading to discontinuation. Number of serious adverse events. • Plasma pharmacokinetics of EMA401 will be characterized by population non-linear mixed effects modeling techniques • Proportion of patients who need rescue medication separately for the double blind treatment epoch and treatment withdrawal epoch, the time to first intake of rescue medication during the double blind treatment epoch |
-Cambio en la puntuación total del Inventario de síntomas del dolor neuropático (NPSI) desde la visita basal hasta la Semana 12 - Cambio en la puntuación total de interferencia del dolor del BPI-SF desde la visita Basal hasta la Semana 12 - Cambio en la media semanal de la puntuación del peor dolor a las 24 horas, utilizando una NRS de 11 puntos, desde la visita Basal hasta la Semana 12 -PGIC en la Semana 12 -Proporción de pacientes que cumplan los criterios de respondedor desde la visita Basal hasta la Semana 12 -Cambio en el ISI desde la visita Basal hasta la Semana 12 -Número y gravedad de los acontecimientos adversos emergentes durante el tratamiento y la frecuencia de acontecimientos adversos que den lugar a la interrupción. Número de acontecimientos adversos graves. -Se caracterizará la farmacocinética de EMA401 en plasma mediante técnicas de modelización de efectos mixtos no lineales. -Proporción de pacientes que necesiten medicación de rescate por separado para la fase de tratamiento doble ciego y la fase de retirada del tratamiento y el tiempo hasta la primera toma de la medicación de rescate durante la fase de tratamiento doble ciego. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For full details, please refer to the schedule of assessments table in the protocol. |
Para más detalles, por favor refiérase a la tabla del calendario abreviado de evaluaciones incluída en el protocolo |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 74 |
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 |
Bulgaria |
Canada |
Denmark |
Finland |
France |
Germany |
Hungary |
Norway |
Poland |
Portugal |
Slovakia |
Spain |
United Kingdom |
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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LVLS |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 4 |
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 | 1 |