E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diagnosis of lower limb spasticity with or without upper limb spasticity of the same body side caused by stroke or traumatic brain injury |
Diagnóstico de la espasticidad de extremidad inferior, con o sin espasticidad de extremidad superior del mismo lado del cuerpo, debida a ictus o traumatismo craneoencefálico |
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E.1.1.1 | Medical condition in easily understood language |
Lower limb or combined lower limb and upper limb spasticity due to stroke or traumatic brain injury |
Espasticidad de extremidad inferior o combinada de extremidades inferior y superior debida a ictus o traumatismo craneoencefálico |
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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 | 10058977 |
E.1.2 | Term | Spastic paresis |
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 |
Evaluation of the efficacy and safety of 400 U of NT 201 in the treatment of adult lower limb spasticity involving the ankle plantar flexors. |
evaluar la eficacia y la seguridad de 400 unidades [U] de NT 201 en el tratamiento de la espasticidad de la extremidad inferior en adultos que afecta a los músculos flexores plantares del tobillo. |
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E.2.2 | Secondary objectives of the trial |
Evaluation of the long-term safety of NT 201 in the treatment of spasticity with total body doses up to 800 U. |
evaluar la seguridad a largo plazo de NT 201 en el tratamiento de la espasticidad con dosis corporales totales de hasta 800 U. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Main inclusion criteria • Female or male subject ≥ 18 years and ≤ 85 years at screening • Diagnosis of lower limb spasticity with or without upper limb spasticity of the same body side caused by stroke or traumatic brain injury • Disabling ankle flexor spasticity presenting as pes equinus or pes equinovarus • Modified Ashworth Scale-Bohannon [MAS] score of 2 or 3 points in the ankle plantar flexor of the target lower limb (supine position, knee extended) • Minimum passive range of motion in ankle of the target lower limb (supine position, knee extended): 10°dorsiflexion and 20°plantarflexion • At least 4 months since last botulinum neurotoxin [BoNT] injection for treatment of spasticity or any other condition • For subjects receiving anticoagulation therapy, the investigator confirms and documents that the subject has an: o Activated partial thromboplastin time [aPTT] ≤ 80 seconds (subjects on dabigatran or other direct thrombin inhibitors) or o International normalized ratio [INR] value of ≤ 2.5 (subjects on coumarins or other anticoagulants monitored by INR)
Main eligibility criteria for re-injection • According to the experience-based opinion of the investigator, the subject must have a clinical need for 400 U of NT 201 in the affected lower limb • Body weight at least 50 kg • Negative urine pregnancy test for women of childbearing potential • For subjects receiving anticoagulation therapy, the investigator confirms and documents that the subject has an: o aPTT ≤ 80 seconds (subjects on dabigatran or other direct thrombin inhibitors) or o INR value of ≤ 2.5 (subjects on coumarins or other anticoagulants monitored by INR) • No infection or inflammation in the area of the planned injection sites at the visits |
Criterios principales de inclusión •Hombres o mujeres ≥18 años y ≤85 años en la selección. •Diagnóstico de espasticidad de la extremidad inferior con o sin espasticidad de la extremidad superior del mismo lado del cuerpo debido a un ictus o a un traumatismo craneoencefálico. •Espasticidad discapacitante de los músculos flexores del tobillo que se presenta en forma de pie equino o pie equinovaro. •Puntuación en la Escala de Ashworth modificada por Bohannon [MAS] de 2 o 3 puntos en los músculos flexores plantares del tobillo de la extremidad inferior diana (posición supina, rodilla extendida). •Rango de movimiento pasivo mínimo del tobillo de la extremidad inferior diana (posición supina, rodilla extendida): 10° de flexión dorsal y 20° de flexión plantar. •Al menos 4 meses desde la última inyección de neurotoxina botulínica [BoNT] para el tratamiento de la espasticidad o cualquier otra afección. •En los sujetos que reciben tratamiento anticoagulante, el investigador debe confirmar y documentar que el sujeto tiene: o Tiempo parcial de tromboplastina activado [aPTT] ≤80 segundos (sujetos que reciben dabigatrán u otros inhibidores directos de trombina) o o Ratio internacional normalizada [INR] ≤2,5 (sujetos que reciben cumarínicos u otros anticoagulantes con control de la INR) Criterios principales de selección para la repetición de la inyección •Según la opinión basada en la experiencia del investigador, el sujeto debe tener una necesidad clínica de 400 U de NT 201 en la extremidad inferior afectada. •Peso corporal mínimo de 50 kg. •Resultado negativo en la prueba de embarazo en orina en las mujeres en edad fértil. •En los sujetos que reciben tratamiento anticoagulante, el investigador debe confirmar y documentar que el sujeto tiene: o aPTT ≤80 segundos (sujetos que reciben dabigatrán u otros inhibidores directos de trombina) o o INR ≤2,5 (sujetos que reciben cumarínicos u otros anticoagulantes con control de la INR) •Sin infección o inflamación en los lugares de inyección previstos en las visitas. |
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E.4 | Principal exclusion criteria |
Main exclusion criteria • Generalized disorders of muscle activity (e.g. myasthenia gravis, Lambert Eaton syndrome, amyotrophic lateral sclerosis) or any other significant peripheral neuromuscular dysfunction which might interfere with the study • Bilateral lower limb paresis/paralysis/spasticity or tetraparesis/paralysis/spasticity • Body weight < 50 kg • Severe atrophy of the target limb muscles • Previous, ongoing or planned treatments of spasticity with intrathecal baclofen • Previous, ongoing, or planned treatments of spasticity in the target lower limb with any of the following procedures: o Surgical intervention o Alcohol or phenol block o Muscle afferent block • Physiotherapy or use of orthoses or splints at the target limb initiated less than 4 weeks before screening or expected to change during the double blind phase of the study • Current or planned treatment with parenterally administered drugs that interfere with neuromuscular transmission (e.g. intrathecal baclofen, tubocurarine type muscle relaxants used in anesthesia),, or local anesthetics in the treated region within 2 weeks prior to screening • Infection or inflammation at the injection sites • Subjects with presence or history of aspiration pneumonia, recurrent lower respiratory tract infections, or compromised respiratory function as per investigator's clinical judgment • Pregnancy (as verified by a positive pregnancy test) or breast feeding |
Criterios principales de exclusión • Trastornos generalizados de la actividad muscular (p. ej. miastenia grave, síndrome de Lambert Eaton, esclerosis lateral amiotrófica) u otra disfunción neuromuscular periférica significativa que pudiera interferir en el estudio. •Paresia/parálisis/espasticidad bilateral de las extremidades inferiores o tetraparesia/parálisis/espasticidad. •Peso corporal <50 kg. •Atrofia grave de los músculos de la extremidad diana. •Tratamientos previos, en curso o previstos para la espasticidad con baclofeno intratecal. •Tratamientos previos, en curso o previstos para la espasticidad de la extremidad inferior diana con alguna de las intervenciones siguientes: o intervención quirúrgica o bloqueo con alcohol o fenol o bloqueo muscular aferente • Fisioterapia o uso de ortesis o férulas en la extremidad diana que se inicia menos de 4 semanas antes de la selección o que se espera que cambie durante la fase doble ciego del estudio. • Tratamiento actual o previsto con medicamentos administrados por vía parenteral que interfieren en la transmisión neuromuscular (p. ej., baclofeno intratecal, relajantes musculares de tipo tubocurarina utilizados en la anestesia) o anestésicos locales en la zona tratada en las 2 semanas anteriores a la selección. • Infección o inflamación en los lugares de inyección. • Sujetos con presencia o antecedentes de neumonía por aspiración, infecciones recurrentes en las vías respiratorias bajas o insuficiencia respiratoria según la opinión clínica del investigador. • Embarazo (verificado mediante un resultado positivo en la prueba de embarazo) o periodo de lactancia. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-primary efficacy variables: • Change from baseline in derived Modified Ashworth Scale-Bohannon (MAS) ankle score (knee extended) • Global Impression of Change Scale (GICS) assessed by physician
Primary safety variable: Occurrence of treatment emergent adverse events [TEAEs] in Main Period |
Criterios de valoración co-principales de la eficacia: • Cambio frente a la Visita Basal en la puntuación de la Escala de Ashworth modificada por Bohannon [MAS] en tobillo (con rodilla extendida) • Global Impression of Change Scale (GICS), evaluada por el médico
Criterio principal de valoración de la seguridad: • Aparición de acontecimientos adversos emergentes durante el tratamiento (treatment emergent adverse events, TEAEs] en el Periodo Principal |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints of evaluation of Co-primary efficacy variables: • Modified Ashworth Scale-Bohannon (MAS) ankle score at Weeks 4 to 6 • Global Impression of Change Scale (GICS) assessed at Week 4 to 6
Timepoint of evaluation of the primary safety variable: • During Main Period |
Momentos de evaluación de los criterios co-principales de valoración de la eficacia: • Puntuación de la Escala de Ashworth modificada por Bohannon [MAS] en tobillo en las Semanas 4 a 6 • Global Impression of Change Scale (GICS) en las Semanas 4 a 6 Momento de evaluación del criterio principal de valoración de la seguridad: • Durante el Periodo Principal |
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E.5.2 | Secondary end point(s) |
Key secondary efficacy variable: • Change from Study Baseline in Goal Attainment Scale [GAS]
Other secondary efficacy variables: • Global Impression of Change Scale (GICS) assessed by subject • Global Impression of Change Scale (GICS) assessed by caregiver |
Criterio de valoración secundario clave de la eficacia: • Cambio frente a la Visita Basal del estudio en la Goal Attainment Scale [GAS]
Otros criterios de valoración secundarios de la eficacia: • Global Impression of Change Scale (GICS) evaluada por el sujeto • Global Impression of Change Scale (GICS) evaluada por el cuidador |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Goal Attainment Scale [GAS] at Week 6 (V4) • GICS assessed by subject at Week 4 (V3) to Week 6 (V4). • GICS assessed by caregiver at Week 4 (V3) to Week 6 (V4). |
• Goal Attainment Scale [GAS] en la Semana 6 (V4) • GICS evaluada por el sujeto desde la Semana 4 (V3) a la Semana 6 (V4). • GICS evaluada por el cuidador desde la Semana 4 (V3) a la Semana 6 (V4) |
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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 | Yes |
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) | 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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Diseño adaptativo en dos etapas con re-evaluación intermedia del tamaño de la muestra tras 360 sujet |
Two-stage adaptive design with interim sample size reassessment after 360 subjects (Treatment/OLEX) |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
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 |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Italy |
Norway |
Poland |
Portugal |
Russian Federation |
Spain |
Switzerland |
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 The End of the entire study, is defined as the date of attendance of the last subject of the final visit of the OLEX period (V17 for subjects with five cycles or V20 with six cycles). |
Última visita del último sujeto. El final de todo el estudio se define como la fecha de la visita final del último sujeto del periodo OLEX (V17 en los sujetos con cinco ciclos o V20 en los sujetos con seis ciclos). |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |