E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heterozygous familial hypercholesterolemia |
Hipercolesterolemia Familiar heterocigótica |
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E.1.1.1 | Medical condition in easily understood language |
Heterozygous familial hypercholesterolemia |
Hipercolesterolemia Familiar heterocigótica |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057079 |
E.1.2 | Term | Heterozygous familial hypercholesterolemia |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Determine whether mipomersen (ISIS 301012) significantly reduces atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (severe HeFH), defined as low-density lipoprotein cholesterol (LDL-C) levels ?200 mg/dL plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ?300 mg/dL regardless of the presence of CHD/risk equivalents (referred to as Cohort 1) compared to placebo. Two different mipomersen dosing regimens will be studied: subcutaneous (SC) mipomersen 200 mg once weekly versus placebo, and SC mipomersen 70 mg thrice weekly versus placebo. |
El objetivo primario de este estudio es determinar si mipomersen (ISIS 301012) reduce de manera significativa las concentraciones de lípidos aterogénicos en los pacientes con hipercolesterolemia familiar heterocigótica grave (HFHe grave), definida como concentraciones de colesterol asociado a lipoproteínas de baja densidad (C-LDL) ?200 mg/dl más la presencia de arteriopatía coronaria (CHD)/equivalentes de riesgo o concentraciones de C-LDL ?300 mg/dl independientemente de la presencia de arteriopatía coronaria (CDC)/equivalentes de riesgo (a los que se hace referencia como Cohorte 1) en comparación con placebo. Se estudiarán dos pautas posológicas diferentes de mipomersen: 200 mg de mipomersen subcutáneo (SC) una vez a la semana en comparación con placebo y 70 mg de mipomersen SC tres veces a la semana en comparación con placebo. |
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E.2.2 | Secondary objectives of the trial |
- Determine whether there are qualitative differences between the safety profiles of the 2 dosing regimens and placebo in Cohort 1, patients with HeFH with LDL-C levels ?160 mg/dL and <200 mg/dL plus the presence of CHD/risk equivalents (referred to as Cohort 2), and the overall study population (comprising patients in both Cohort 1 and Cohort 2) - Determine whether there are qualitative differences between the tolerability of the 2 dosing regimens and placebo in Cohort 1, Cohort 2, and the overall study population -Further characterize the pharmacokinetics (PK) of the 2 dosing regimens in Cohort 1, Cohort 2, and the overall study population - Determine whether the 2 mipomersen dosing regimens significantly reduce atherogenic lipid levels in Cohort 2 compared to placebo |
-Determinar si existen diferencias cualitativas entre los perfiles de seguridad de las dos pautas posológicas y el placebo en la cohorte 1, pacientes con HFHe con concentraciones de C-LDL ?160 mg/dl y <200 mg/dl más la presencia de arteriopatía coronaria /de equivalentes de riesgo (a los que se hace referencia como la cohorte 2) y la población general del estudio (que abarca pacientes de la cohorte 1 y la cohorte 2) -Determinar si existen diferencias cualitativas entre la tolerabilidad de las dos pautas posológicas y el placebo en la cohorte 1, la cohorte 2 y la población general del estudio -Además determinar la farmacocinética (FC) de las dos pautas posológicas en la cohorte 1, la cohorte 2 y la población general del estudio -Determinar si las dos pautas posológicas de mipomersen reducen de manera significativa las concentraciones de lípidos aterogénicos en la cohorte 2 en comparación con el placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Diagnosis of severe hypercholesterolemia (LDL-C ?300 mg/dL (7.77 mmol/L) or LDL-C ? 200 mg/dL (5.18 mmol/L) and documented coronary heart disease (CHD) or CHD risk equivalent or diagnosis of Heterozygous Familial Hypercholesterolemia and LDL-C ?160 mg/dL (4.14 mmol/L) and <200 mg/dL (5.18 mmol/L)) On stable, maximally tolerated, statin therapy for at least 12 weeks or if statin intolerant, on at least 1 medication from another class of hypolipidemic agents (i.e., bile acid sequestrants, niacin/nicotinic acid, cholesterol absorption inhibitors, fibrates). On stable, low fat diet for 12 weeks Body mass index (BMI) ?40 kg/m2 and stable weight for 6 weeks |
Diagnostico de Hipercolesterolemia servera (LDL-C ?300 mg/dL (7.77 mmol/L) o LDL-C ? 200 mg/dL (5.18 mmol/L) y en presencia de arteriopatía coronaria o equivalentes de riesgo o diagnósitico de Hipercolesterolemia Heterocigotica Familiar y LDL-C ?160 mg/dL (4.14 mmol/L) y <200 mg/dL (5.18 mmol/L)) El paciente está en tratamiento estable con máxima dosis de estatinas durante al menos doce semanas antes del screening o en caso de intolerancia a las estatinas en tratamiento con al menos un hipolipemiante (es decir, secuestradores de ácidos biliares, niacina/ácido nicotínico, inhibidores de la absorción de colesterol, fibratos). El paciente está en una dieta estable baja en grasas durante al menos 12 semanas antes de screening y presenta un índice de masa corporal ?40 kg/m2 con peso estable (± 4 kg) durante >6 semanas antes del Screening. |
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E.4 | Principal exclusion criteria |
Significant health problems in the recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, hypertension, blood disorders, liver disease, cancer, digestive disorders, Type I diabetes, or uncontrolled Type II diabetes Apheresis within 3 months prior to Screening or expected to start apheresis during the treatment phase |
El paciente ha tenido problemas cardiacos en el pasado, sufrido un IM, una intervención coronaria transluminal percutánea, CABG, un accidente cerebrovascular, angina de pecho inestable, un síndrome coronario agudo, arritmia clínicamente significativa, hipertensión, hepatopatía clínicamente significativa, problemas hepáticos, cancer, desordenes digestivos, diabetes mellitus (tipo 1) insulinodependiente, o diabetes de tipo 2 hemoglobina A glucosilada (HbA1c; glucohemoglobina) >8% en el screening. El paciente se ha sometido a aféresis en los tres meses previos al screening o tiene previsto comenzar la aféresis durante la fase de tratamiento |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent change from Baseline in low-density lipoprotein cholesterol in Cohort 1 |
Cambio porcentual desde el basal en C-LDL en la cohorte 1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to Week 60 |
Basal a la semana 60 |
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E.5.2 | Secondary end point(s) |
Percent change from Baseline in Apolipoprotein Percent change from Baseline in Lipoprotein a Percent change from Baseline in low-density lipoprotein cholesterol in Cohort 2 Number of Participants with Adverse Events Number of Participants with injection site reactions Blood plasma concentration of Mipomersen |
Cambio porcentual desde el basal en Apolipoproteina Cambio porcentual desde el basal en Lipoproteina a Cambio porcentual desde el basal en C-LDL en la cohorte 2 Número de participantes con acontecimientos adversos Número de participantes con reacciones en puntos de inyección Concentración plasmática de Mipomersen |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Percent change from Baseline in Apolipoprotein : Baseline to Week 60 Percent change from Baseline in Lipoprotein a : Baseline to Week 60 Percent change from Baseline in low-density lipoprotein cholesterol in Cohort 2 : Baseline to Week 60 Number of Participants with Adverse Events : 60 weeks Number of Participants with injection site reactions : 60 weeks Blood plasma concentration of Mipomersen : Pre-dose and at 2, 4, 6, 24, 48 and 72 hours post-dose at Weeks 1, 30, 36 and 60. |
Cambio porcentual desde el basal en Apolipoproteina: Basal a semana 60 Cambio porcentual desde el basal en Lipoproteina a: basal a semana 60 Cambio porcentual desde el basal en C-LDL en la cohorte 2: basal a semana 60 Número de participantes con acontecimientos adversos: basal a semana 60 Número de participantes con reacciones en puntos de inyección: basal a semana 60 Concentración plasmática de Mipomersen: pre-dosis y a las 2, 4, 6, 24, 48 y 72 horas post-dosis en las semanas 1, 30, 36 y 60 |
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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 | 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 | 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 | 4 |
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 | 61 |
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 |
Canada |
Croatia |
Hong Kong |
India |
Israel |
Malaysia |
New Zealand |
Norway |
Russian Federation |
South Africa |
Taiwan |
Turkey |
Ukraine |
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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Last visit of the last subject |
ultima visita del último paciente |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |