E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Duchenne Muscular Dystrophy |
Distrofia muscular de Duchenne |
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E.1.1.1 | Medical condition in easily understood language |
Duchenne Muscular Dystrophy (DMD) |
Distrofia muscular de Duchenne (DMD) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10013801 |
E.1.2 | Term | Duchenne muscular dystrophy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
To evaluate the long term safety, tolerability and efficacy of subcutaneous 6mg/kg/week GSK2402968 in subjects with DMD who have participated in either DMD114117 or DMD114044. |
Evaluar la seguridad, tolerabilidad y eficacia a largo plazo de GSK2402968 6 mg/kg/semana SC en sujetos con DMD que hayan participado en los estudios DMD114117 o DMD114044. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the long-term PK of subcutaneous 6 mg/kg/week GSK2402968 in subjects with DMD who have participated in either DMD114117 or DMD114044. - To evaluate the long-term impact on health-related quality of life (HRQoL) and functional outcomes of continued treatment with GSK2402968 in subjects with DMD who have participated in either DMD114117 or DMD114044. -To evaluate DMD disease progression and outcomes (clinical, HRQoL and functional) in subjects who discontinue active treatment during the conduct of study (natural history component). - To evaluate the long-term safety, efficacy and PK of an intermittent dosing option in those subjects unable to tolerate GSK2402968 6mg/kg/week dosing. |
- Evaluar la FC (farmacocinética) a largo plazo de GSK2402968 6 mg/kg/semana por vía SC en sujetos con DMD que hayan participado en los estudios DMD114117 o DMD114044. - Evaluar el impacto a largo plazo sobre la calidad de vida relacionada con la salud (CdVRS) y los resultados funcionales del tratamiento continuado con GSK2402968 en sujetos con DMD que hayan participado en los estudios DMD114117 o DMD114044. - Evaluar la progresión de la enfermedad y los resultados (clínicos, CdVRS y funcionales) en la DMD en los sujetos que interrumpan el tratamiento activo durante el estudio (componente de observación de la historia natural de la enfermedad). - Evaluar la seguridad, eficacia y FC a largo plazo de una dosis intermitente en los sujetos que no toleren la dosis de GSK2402968 6mg/kg/semana. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria: 1. Subjects who have successfully completed either the DMD114117 study or DMD114044 study, OR Subjects who withdrew due to safety/tolerability issues, which have since resolved and where in the opinion of the PI along with consultation of the Medical Monitor, it is considered that the benefit of further treatment with GSK2402968 outweighs the risk to the individual subject. OR Subjects who either complete or withdraw early from studies DMD114117 or DMD114044, who do not wish to continue treatment with GSK2402968 but who are willing to participate in the natural history observation arm. 2. Continued use of glucocorticoids with a reasonable expectation that the subject will remain on steroids for the duration of the study. Changes to or cessation of glucocorticosteroids will be at the discretion of the PI in consultation with the subject/parent and the Medical Monitor. 3. Willing and able to comply with all protocol requirements and procedures, 4. Able to give informed assent and/or consent in writing signed by the subject and/or parent(s)/legal guardian (according to local regulations). 5. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
Los sujetos deberán cumplir todos los criterios siguientes para poder ser incluidos en el estudio: 1. Sujetos que hayan completado con éxito el estudio DMD114117 o el estudio DMD114044, O BIEN Sujetos que se hayan retirado por problemas de seguridad/tolerabilidad que ya se hayan resuelto y en los que, en opinión del IP en consulta con el monitor médico, se considere que el beneficio del tratamiento con GSK2402968 supera a los riesgos para el sujeto. O BIEN Sujetos que hayan completado o se hayan retirado prematuramente de los estudios DMD114117 o DMD114044 y no deseen continuar el tratamiento con GSK2402968 pero quieran participar en el grupo de observación de la historia natural de la enfermedad. 2. Uso continuo de glucocorticoides con previsión razonable de que el sujeto siga tomándolos durante el estudio. Los cambios o la interrupción de los glucocorticoides quedarán a discreción del IP, en consulta con el sujeto/progenitor y el monitor médico. 3. Disposición y capacidad para cumplir todos los requisitos y procedimientos del protocolo, 4. Capacidad para dar el asentimiento o consentimiento informado por escrito, firmado por el sujeto o su progenitor o tutor legal (de acuerdo con las leyes locales). 5. Sujetos franceses: En Francia sólo se podrá incluir en este estudio a los sujetos afiliados o beneficiarios de alguna categoría de la seguridad social. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study: 1. Subject had a serious adverse experience or who met safety stopping criteria that remains unresolved from DMD114117 or DMD114044, which in the opinion of the investigator could have been attributable to study medication, and which is ongoing at Visit 2. Once resolved, subject may be eligible to enrol following PI consultation with the Medical Monitor. 2. Use of anticoagulants, antithrombotics or antiplatelet agents, or previous treatment with investigational drugs except for GSK2402968, within 1 month of the first administration of study medication. 3. Current or anticipated participation in any other investigational clinical studies 4. History of significant medical disorder which may confound the interpretation of either efficacy or safety data e.g. current or history of renal or liver disease/impairment, history of inflammatory illness. |
No se incluirá en el estudio a los sujetos que cumplan alguno de los criterios siguientes: 1. Sujetos con un acontecimiento adverso grave o en los que se haya cumplido alguno de los criterios de interrupción de la administración del fármaco en los estudios DMD114117 o DMD114044 y continúe sin resolverse, siempre que, en opinión del investigador, pueda atribuirse a la medicación del estudio y que continúe en la visita 2. Una vez resuelto el acontecimiento o criterio, los sujetos podrán participar, previa consulta del IP con el monitor médico. 2. Uso de anticoagulantes, antitrombóticos o antiplaquetarios, o tratamiento previo con fármacos en investigación, excepto GSK2402968, en el mes previo a la primera administración del fármaco del estudio. 3. Participación actual o prevista en otros estudios clínicos de investigación. 4. Antecedentes de trastorno médico importante que pueda confundir la interpretación de los datos de eficacia o de seguridad, como enfermedad/insuficiencia renal o hepática actual o previa, o antecedentes de enfermedad inflamatoria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint: - Muscle function using 6 minute walking distance (6MWD) test. |
Variable principal de valoración de la eficacia: - Función muscular utilizando la prueba prueba TM6M (distancia caminada en 6 minutos) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Weeks 12,24,48,72 and Week 104 or Early withdrawal |
Semanas 12, 24, 48, 72 y Semana 104 o Visita de retirada prematura. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints: -Timed function tests (times and grading): . Rise from floor . 4 stair climb . 10m walk/run - Muscle strength (total score): knee flexors, knee extensors, elbow flexors, elbow extensors, shoulder abductors and hip flexors (as determined by handheld myometery) - North Star Ambulatory Assessment - Creatine kinase serum concentrations - Pulmonary function (FEV1, FVC, PCF, PF, sniff pressure test) - Pediatric Quality of Life Neuromuscular module (PedsQL) - Clinician Global Impression of Improvement (CGI-I) - Health Utilities Index (HUI) - Time to major disease milestones (e.g. loss of ambulation, night time ventilation) - Frequency of accidental falls (during 6MWD) - Functional Outcomes assessment Safety endpoints: - Incidence and severity of adverse events. - Vital signs - ECG parameters - Safety haematology and biochemistry parameters including non-standard parameters such as coagulation parameters (in particular aPTT), serum cystatin C, Complement Factor C3, haptoglobin, fibrinogen, hsCRP, MCP-1 - Urinalysis (including quantitative protein, creatinine and ratio, urine cystatin, KIM-1 and ?1-microglobulin) - Echocardiogram Pharmacokinetics: - AUC[0-24], AUC[0-7d], - Cmax - tmax - C24h, - C7d, DEXA Scan Lean body mass and bone density (exploratory endpoint) MRI Assess changes in fat infiltration and oedematous inflammation in skeletal muscle in the thigh as determined by structural MRI measures over time in those subjects who had a baseline MRI in the DMD114044 study. |
Variables secundarias de la eficacia: - Pruebas funcionales cronometradas (tiempos y puntuación): . Levantarse del suelo . Subir 4 escalones . Marchar/correr 10 m - Fuerza muscular (puntuación total): flexores de la rodilla, extensores de la rodilla, flexores del codo, extensores del codo, abductores del hombro y flexores de la cadera (lo que se determine mediante miometría manual) - North Star Ambulatory Assessment (Evaluación Ambulatoria North Star) - Concentraciones de creatina quinasa en suero - Pruebas de la función pulmonar (FEV1, FVC, PCF, PF, Test de presión inspiratoria-Sniff pressure test) - Módulo neuromuscular de calidad de vida pediátrica (PedsQL) - Impresión clínica global de mejoría (CGI-I) - Índice de utilidades de salud (HUI) - Tiempo hasta los principales hitos de la enfermedad (por ejemplo, pérdida de ambulación, ventilación nocturna) - Frecuencia de caídas accidentales (durante el TM6M) - Evaluación de los resultados funcionales
Variables de seguridad: - Incidencia y gravedad de los acontecimientos adversos - Constantes vitales - Parámetros del ECG - Parámetros hematológicos y bioquímicos de seguridad, incluidos parámetros no habituales como los de coagulación (en particular, el TTPa), cistatina C en suero, factor del complemento C3, haptoglobina, fibrinógeno, PCRas, MCP-1 - Análisis de orina (con cuantificación de proteínas, creatinina y proporción proteína/creatinina, cistatina en orina, KIM-1 y alfa1-microglobulina) - Ecocardiograma Farmacocinética: - AUC[0-24], AUC[0-7d], - Cmáx - tmáx - C24h, - C7d, DEXA Scan Masa corporal magra y densidad ósea (variable exploratoria) RM (Resonancia Magnética) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Functional secondary endpoints and collection of questionnaires will be performed at the same intervals as the primary endpoint. Samples for urinalysis and safety labs will be collected Baseline and every two weeks thereafter till visit 104 or Early withdrawal. Predose PK samples will be collected monthly. Serial PK at either Week 12 or 48: prior to treatment and 1/2, 2, 4 hours and between 9-12 hours and 48-72 hours after treatment. Vital signs & ECG Weeks 4,8,16,24,32,40,48,60,72,84,96, and Week 104 or Early withdrawal. Echo & DEXA: Weeks 24, 48, 72, and Week 104 or Early withdrawal. |
Las variables secundarias funcionales y los cuestionarios se realizarán en los mismos puntos que la variable principal. Las muestras para análisis de orina y muestras de laboratorio de seguridad se recogerán en la visita basal y cada dos semanas a partir de entonces hasta la visita de la semana 104 o la visita de retirada prematura. Las muestras FC predosis se recogerán una vez al mes. La FC seriada en la semana 12 o 48: antes de la dosis y después de la dosis a las siguientes horas: 0.5, 2, 4 horas, entre 9-12 horas, 24 horas y entre 48 72 horas. Los signos vitales y ECG: semanas 4,8,16, 24,32, 40, 48, 60, 72, 84, 96 y semana 104 o retirada prematura. Ecocardiograma y DEXA: semanas 24, 48, 72 y semana 104 o retirada prematura. |
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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 | 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) | 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 | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
Belgium |
Brazil |
Canada |
Chile |
Czech Republic |
Denmark |
France |
Germany |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Norway |
Poland |
Russian Federation |
Spain |
Taiwan |
Turkey |
United Kingdom |
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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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This study has a duration of a minimum of 2 years or until treatment is commercially available locally. |
Este estudio durará 2 años como mínimo o hasta que esté comercialmente disponible el tratamiento localmente. |
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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 | 2 |
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 | 2 |
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 |