E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypercholesterolaemia |
Hipercolesterolemia |
|
E.1.1.1 | Medical condition in easily understood language |
Hypercholesterolaemia |
Hipercolesterolemia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020603 |
E.1.2 | Term | Hypercholesterolaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 evaluate the efficacy of alirocumab administered every 2 weeks (Q2W) versus placebo after 24 weeks of double-blind (DB) treatment on low-density lipoprotein cholesterol (LDL-C) levels in patients with heterozygous familial hypercholesterolemia (heFH) 8 to 17 years of age on optimal stable daily dose of statin therapy ± other lipid modifying therapies (LMTs) or a stable dose of nonstatin LMTs in case of intolerance to statins. |
Evaluar la eficacia de alirocumab administrado cada 2 semanas (C2S) frente a placebo después de 24 semanas de tratamiento con doble enmascaramiento (DE) sobre las concentraciones de colesterol transportado por lipoproteínas de baja densidad (C-LDL) en pacientes con hipercolesterolemia familiar heterocigótica (HFhe) de 8 a 17 años de edad tratados con una dosis óptima estable diaria de estatinas ± otros tratamientos modificadores de los lípidos (TML) o con una dosis estable de TML no estatínico en caso de intolerancia a las estatinas. |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of alirocumab versus placebo on low-density lipoprotein cholesterol (LDL-C) levels. -To evaluate the effects of alirocumab versus placebo on other lipid parameters. -To evaluate the safety and tolerability of alirocumab in comparison with placebo. -To evaluate the efficacy, safety, and tolerability of alirocumab after open label treatment. -To evaluate the development of anti-alirocumab antibodies. |
- Evaluar la eficacia de alirocumab frente a placebo sobre las concentraciones de C-LDL después de 12 semanas de tratamiento con DE. - Evaluar los efectos de alirocumab frente a placebo sobre otros parámetros lipídicos - Evaluar la seguridad y la tolerabilidad de alirocumab después de 24 semanas de tratamiento en comparación con placebo. - Evaluar la eficacia, la seguridad y la tolerabilidad de alirocumab después de 80 semanas de tratamiento en abierto. - Evaluar el desarrollo de anticuerpos antialirocumab después de 24 semanas de tratamiento durante el periodo de tratamiento con doble enmascaramiento. |
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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 |
A non-invasive flow mediated dilatation assessment will be part of a substudy (n=30 to 39) performed at selected sites. |
Subestudio de dilatación mediada por el flujo (DMF), (n = 30 a 39) realizado en centros seleccionados. |
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E.3 | Principal inclusion criteria |
-Children and adolescent male and female patients aged 8 to 17 years at the time of signed informed consent. -Patients with diagnosis of heterozygous familial hypercholesterolemia (heFH) through genotyping or clinical criteria. -Patients treated with optimal dose of statin +/- other LMT(s) or non-statin LMT(s) if statin intolerant at stable dose for at least 4 weeks prior to screening lipid sampling. -Patients with calculated LDL-C greater than or equal to 130 mg/dL (≥3.37 mmol/L) at the screening visit except for patients who have previously participated in the DFI14223 study. -A signed informed consent indicating parental permission with or without patient assent. |
- Niños y adolescentes de ambos sexos de edades de entre 8 y 17 años en el momento del consentimiento informado firmado. - Pacientes con diagnóstico de hipercolesterolemia familiar heterocigota (HFhe) a través del genotipo o criterios clínicos. - Pacientes tratados con dosis óptimas de estatinas +/- otros TML (s) o TML (s) sin estatina (s) si no toleran estatinas a dosis estables durante al menos 4 semanas antes de la analítica de selección de los lípidos. - Pacientes con LDL-C calculado mayor o igual a 130 mg / dL (≥3.37 mmol / L) en la visita de selección, excepto para los pacientes que participaron previamente en el estudio DFI14223. -Un consentimiento informado firmado que indica el permiso de los padres con o sin asentimiento del paciente. |
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E.4 | Principal exclusion criteria |
-Patient with body weight less than 25 kg. -Patients aged of 8 to 9 years not at Tanner stage 1 and patients aged of 10 to 17 years not at least at Tanner stage 2 in their development. -Patients with secondary hyperlipidemia. -Diagnosis of homozygous familial hypercholesterolemia. -Patient who has received lipid apheresis treatment within 2 months prior to the screening period, or has plans to receive it during the study. -Patients with uncontrolled type 1 or type 2 diabetes mellitus. -Patients with known uncontrolled thyroid disease. -Patients with uncontrolled hypertension. -Fasting triglycerides >350 mg/dL (3.95 mmol/L). -Severe renal impairment (ie, estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m^2. -Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 x upper limit of normal (ULN). -Creatinine phosphokinase (CPK) >3 x ULN. |
-Paciente con un peso corporal inferior a 25 kg. - Los pacientes con edades comprendidas entre 8 y 9 años no en estadío 1 de Tanner y los pacientes con edades comprendidas entre 10 y 17 años, al menos en estadío 2 de Tanner en su desarrollo. - Pacientes con hiperlipidemia secundaria. -Diagnóstico de hipercolesterolemia familiar homocigótica. - Paciente que ha recibido tratamiento de aféresis lipídica dentro de los 2 meses previos al período de selección o tiene planes para recibirlo durante el estudio. - Pacientes con diabetes mellitus tipo 1 o tipo 2 no controlada. - Pacientes con enfermedad tiroidea descontrolada conocida. - Pacientes con hipertensión no controlada. -Triglicéridos en ayunas >350 mg/dl (3,95 mmol/l) en la visita de selección. - Insuficiencia renal grave (es decir, tasa de filtración glomerular estimada [TFGe] <30 ml / min / 1,73 m2 -Alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST)> 2 x límite superior de la normalidad (LSN). -Creatinina fosfokinasa (CPK)> 3 x ULN. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent change in low-density lipoprotein cholesterol (LDL-C): Percent change in LDL-C from baseline to Week 24 |
Cambio porcentual en el C-LDL desde el inicio hasta la Semana 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to Week 24 |
Desde el inicio hasta la Semana 24 |
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E.5.2 | Secondary end point(s) |
1) Percent change in LDL-C: Percent change in LDL-C 2) Percent change in Apo B: Percent change in Apo B 3) Percent change in non-high density lipoprotein cholesterol (non HDL-C): Percent change in non-HDL-C 4) Percent change in Total-C: Percent change in Total-C 5) Patients with LDL-C level <130 mg/dL (3.37 mmol/L): Proportion of patients with LDL-C level < 130 mg/dL (3.37 mmol/L) at Week 12 and at Week 24 6) Patients with LDL-C level <110 mg/dL (2.84 mmol/L): Proportion of patients with LDL-C level < 110 mg/dL (2.84 mmol/L) at Week 12 and at Week 24 7) Percent change in Lp(a): Percent change in lipoprotein (a) from baseline to Week 12 and to Week 24 8) Percent change in HDL-C: Percent change in HDL-C from baseline to Week 12 and to Week 24 9) Percent change in TG: Percent change in fasting triglycerides (TG) from baseline to Week 12 and to Week 24 10) Percent change in Apo A-1: Percent change in apolipoprotein A1 (Apo A-1) from baseline to Week 12 and to Week 24 11) Number of patients with adverse events: Number of patients with adverse events 12) Cogstate battery test: The Cogstate battery test will assess maturing cognition across a broad number of key developmental functions 13) Tanner stage: The Tanner stages will be measured to assess stages of pubertal development |
1) Cambio porcentual en LDL-C: cambio porcentual en LDL-C 2) Cambio porcentual en Apo B: cambio porcentual en Apo B 3) Cambio porcentual en el colesterol de lipoproteínas de alta densidad (no HDL-C): cambio porcentual en no HDL-C 4) Cambio porcentual en Total-C: cambio porcentual en Total-C 5) Pacientes con niveles de c-LDL <130 mg / dl (3,37 mmol / l): Proporción de pacientes con niveles de c-LDL <130 mg / dl (3,37 mmol / l) en la semana 12 y en la semana 24 6) Pacientes con niveles de LDL-C <110 mg / dL (2,84 mmol / L): Proporción de pacientes con niveles de LDL-C <110 mg / dL (2,84 mmol / L) en la Semana 12 y en la Semana 24 7) Cambio porcentual en Lp (a): cambio porcentual en la lipoproteína (a) desde el inicio hasta la semana 12 y hasta la semana 24 8) Cambio porcentual en HDL-C: cambio porcentual en HDL-C desde el inicio hasta la semana 12 y hasta la semana 24 9) Cambio porcentual en TG: cambio porcentual en los triglicéridos en ayunas (TG) desde el inicio hasta la semana 12 y hasta la semana 24 10) Cambio porcentual en Apo A-1: cambio porcentual en la apolipoproteína A1 (Apo A-1) desde el inicio hasta la semana 12 y hasta la semana 24 11) Número de pacientes con acontecimientos adversos: Número de pacientes con acontecimientos adversos 12) Batería de pruebas Cogstate: la batería de pruebas Cogstate evaluará la cognición de maduración en un amplio número de funciones clave de desarrollo 13) Estadíos de Tanner: los estadíos de Tanner se medirán para evaluar las etapas del desarrollo puberal |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) From baseline to Week 12 2) to 10) From baseline to Week 12 and to Week 24 11) Up to Week 104 12) A Day 1, Weeks 24, 68, and 104 13) At Weeks 24, 44, 68, and 104 |
1) Desde el inicio hasta la semana 12 2) a 10) Desde el inicio hasta la Semana 12 y hasta la Semana 24 11) Hasta la semana 104 12) A día 1, semanas 24, 68 y 104 13) En las semanas 24, 44, 68 y 104 |
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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 | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
heFH genotyping |
Genotipado de hipercolesterolemia familiar heterocigótica (HFhe) |
|
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 | 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 | 26 |
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 |
Austria |
Brazil |
Bulgaria |
Canada |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Hungary |
Italy |
Lebanon |
Mexico |
Netherlands |
Norway |
Poland |
Russian Federation |
South Africa |
Spain |
Sweden |
Taiwan |
Turkey |
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
|
LVLS |
Última visita del último paciente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |