E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Non-familial hypercholesterolemia or heterozygous familial hypercholesterolemia (heFH)at high CV risk who are not adequately controlled with atorvastatin (20 mg or 40 mg), with or without other Lipid-modifying therapy (LMT)(excluding EZE). |
Pazienti con ipercolesterolemia non familiare o ipercolesterolemia familiare eterozigote (heFH) ad alto rischio CV che non sono adeguatamente controllati con atorvastatina (20 mg o 40 mg) con o senza altra terapia modificante dei lipidi (LMT) (escluso EZE). |
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E.1.1.1 | Medical condition in easily understood language |
High blood cholesterol level |
Alto livello di colesterolo nel sangue |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
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 reduction of low-density lipoprotein cholesterol (LDL-C) by REGN727 as add-on therapy to atorvastatin in comparison with ezetimibe (EZE) as add-on therapy to atorvastatin, in comparison with doubling the atorvastatin dose, or in comparison with a therapy switch from atorvastatin to rosuvastatin, after 24 weeks of treatment. |
Valutare la riduzione del colesterolo delle lipoproteine a bassa densità (C-LDL) da parte di REGN727 come terapia di associazione con atorvastatina in confronto con ezetimibe (EZE) come terapia di associazione con atorvastatina, in confronto con il raddoppio della dose di atorvastatina, o in confronto con un passaggio dalla terapia con atorvastatina a quella con rosuvastatina, dopo 24 settimane di trattamento |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the reduction of LDL-C by REGN727 75 mg as add-on therapy to atorvastatin in comparison with EZE as add-on therapy to atorvastatin, in comparison with doubling of the atorvastatin dose, or in comparison with a switch from atorvastatin to rosuvastatin after 12 weeks of treatment. -To evaluate the effect of REGN727 on other lipid parameters eg, apolipoprotein (Apo) B, non-high-density lipoprotein cholesterol (HDL-C), total-cholesterol (C), lipoprotein a (Lp[a]), HDL-C, triglycerides (TG) levels, and ApoA-1 levels. -To evaluate the safety and tolerability of REGN727. -To evaluate the development of anti-REGN727 drug antibodies (ADA). |
-Valutare la riduzione di C-LDL da parte di REGN727 75 mg come terapia di associazione con atorvastatina in confronto con EZE come terapia di associazione con atorvastatina, in confronto con il raddoppio della dose di atorvastatina o un passaggio dalla atorvastatina alla rosuvastatina dopo 12 settimane di trattamento. -Valutare l'effetto di REGN727 su altri parametri dei lipidi, ad es. apolipoproteina (Apo)B, colesterolo non-HDL (C-HDL), colesterolo totale (C), lipoproteina a (Lp[a]), C-HDL, livelli dei trigliceridi (TG) e di ApoA-1. -Valutare la sicurezza e la tollerabilità di REGN727. -Valutare lo sviluppo di anticorpi anti-REGN727 (ADA). |
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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 |
PHARMACOGENOMIC: Vers:1 Date:2012/06/26 Title:A Randomized, Double-Blind Study of the Efficacy and Safety of REGN727 Added-on to Atorvastatin versus Ezetimibe Added-on to Atorvastatin versus Atorvastatin Dose Increase versus Switch to Rosuvastatin in Patients Who are Not Controlled on Atorvastatin Objectives:To identify genetic associations with clinical or biomarker response to PCSK9 inhibition,hyperlipidemia, or CVD. If needed, samples may also be used to identify markers associated with toxicity.
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FARMACOGENOMICA: Vers:1 Data:2012/06/26 Titolo:Studio clinico randomizzato in doppio cieco sull'efficacia e la sicurezza di REGN727 in associazione ad atorvastatina rispetto alla terapia di associazione con ezetimibe e atorvastatina, a un aumento del dosaggio dell'atorvastatina e al passaggio a rosuvastatina in pazienti non controllati con atorvastatina Obiettivi:Identificare le associazioni genetiche con risposta clinica o a livello di biomarker per inibizione di PCSK9, iperlipidemia, o CVD. Se necessario, i campioni possono anche essere utilizzati per identificare marcatori associati a tossicità.
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E.3 | Principal inclusion criteria |
1. A patient must meet either 1a or 1b to be eligible for inclusion in the study: a. Patients with screening (visit 1) LDL-C ≥70 mg/dL (1.81 mmol/L) who are not adequately controlled with a 20 mg or 40 mg stable daily dose of atorvastatin for at least 4 weeks before the screening visit (visit 1), with or without other LMT (excluding EZE). Patients with heFH* or non-FH must also have a history of documented CHD (defined below), or non-CHD CVD (defined below), or diabetes mellitus with target organ damage. OR b. Patients with screening (visit 1) LDL-C ≥100 mg/dL (2.59 mmol/L) who are not adequately controlled with a 20 mg or 40 mg daily dose of atorvastatin for at least 4 weeks before the screening visit (visit 1), with or without other LMT (excluding EZE). Patients must also have heFH*, or have non-FH, without CHD or non-CHD CVD, but with a calculated 10-year fatal CVD risk SCORE ≥5%, or with moderate CKD, or with diabetes mellitus but no target organ damage. Note: Details for the inclusion criteria are provided below. 2. Provide signed informed consent |
1. Un paziente deve soddisfare sia 1a o 1b per essere eleggibile all'inclusione nello studio: a. I pazienti con screening (visita 1) C-LDL ≥ 70 mg / dL (1,81 mmol / L) che non sono adeguatamente controllati con una dose di 20 mg o 40 mg al giorno di atorvastatina stabile per almeno 4 settimane prima della visita di screening (visita 1 ), con o senza altre LMT (escluso EZE). I pazienti con heFH* o non-FH devono anche avere una storia di CHD documentata (definito di seguito), o non-CHD CVD (definito di seguito), o diabete mellito con danno d'organo. O b. I pazienti con screening (visita 1) C-LDL ≥ 100 mg / dL (2,59 mmol / L) che non sono adeguatamente controllati con una dose di 20 mg o 40 mg al giorno di atorvastatina per almeno 4 settimane prima della visita di screening (visita 1) , con o senza altre LMT (escluso EZE). I pazienti devono anche avere heFH*, o avere non-FH, senza CHD o non CHD CVD, ma con un rischio SCORE ≥ 5% a 10 anni di CVD fatale , o con CKD moderata, o con diabete mellito, ma non danno d'organo bersaglio . Nota: Dettagli per i criteri di inclusione sono fornite di seguito. 2. Fornire il consenso informato firmato. |
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E.4 | Principal exclusion criteria |
LDL-C <70mg/dL (<1.81 mmol/L) in patients with CVD;LDL-C <100mg/dL (<2.59 mmol/L) in patients without CVD, but with other risk factors;LDL-C >250mg/dL or TG>400mg/dL;Homozygous FH or patients receiving plasmapheresis;CV event within 3 months prior to screening;NYHA Class III or IV heart failure;History of hemorrhagic stroke;Uncontrolled endocrine disease known to influence serum lipids;any clinically significant abnormality that in the judgment of the investigator would preclude safe completion of the study or constrain endpoints assessment such as major systemic diseases, patients withshort life expectancy,patients who can not tolerate subcutaneous injections;Use of ezetimibe or red yeast rice products within 4 weeks of screening;Use of systemic corticosteroids or use of fibrates,other than fenofibrate within 6 weeks of the screening;eGFR <30mL/min/1.73m2;ALT or AST aminotransferase >3 x upper limit of normal (ULN); CPK >3 x ULN;TSH <lower limit of normal (LLN);Hypersensitivity to monoclonal antibody therapeutics; Pregnant or breast-feeding women;Women of childbearing potential with no effective contraceptive method of birth control. |
LDL-C <70mg/dL (<1,81 mmol / l) in pazienti con CVD;LDL-C <100mg/dL (<2,59 mmol / l) in pazienti senza CVD, ma con altri fattori di rischio;LDL-C> 250mg/dL o TG> 400mg/dL; FH omozigote o pazienti trattati con plasmaferesi; eventi CV nei 3 mesi precedenti lo screening;Classe NYHA III o IV, insufficienza cardiaca;Storia di ictus emorragico;Malattia endocrina non controllata nota influenzare lipidi sierici;qualsiasi anomalia clinicamente significativa che,a giudizio dello sperimentatore, precluderebbe il completamento sicuro dello studio o possa limitare la valutazione di endpoints come le principali malattie sistemiche, i pazienti con breve aspettativa di vita, i pazienti che non tollerano iniezioni sottocutanee;L'uso di ezetimibe o prodotti contenenti lievito di riso rosso entro 4 settimane di screening;L'uso di corticosteroidi sistemici o l'uso di fibrati, oltre fenofibrato entro 6 settimane di screening;eGFR <30mL/min/1.73m2;ALT o AST aminotransferasi > 3 volte il limite superiore della norma (ULN);CPK> 3 x ULN;TSH <limite inferiore di normalità (LLN);Ipersensibilità alle terapie con anticorpi monoclonali;Donne in gravidanza o in allattamento;Le donne in età fertile con nessun metodo contraccettivo efficace di controllo delle nascite. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the percent change in calculated LDL-C from baseline to week 24,which is defined as: 100x (calculated LDL-C value at week 24 - calculated LDL-C value at baseline)/calculated LDL-C value at baseline. |
L'endpoint primario di efficacia è la variazione percentuale del C-LDL calcolata dal basale alla settimana 24, definita come: 100x (valore LDL-C calcolato alla settimana 24 - valore LDL-C calcolato al baseline / valore LDL-C calcolato al baseline. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to week 24 |
Dal baseline alla settimana 24 |
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E.5.2 | Secondary end point(s) |
-The percent change in calculated LDL-C from baseline to week 12 -The percent change in ApoB from baseline to week 24. -The percent change in non-HDL-C from baseline to week 24. -The percent change in total-C from baseline to week 24. -The percent change in ApoB from baseline to week 12. -The percent change in non-HDL-C from baseline to week 12. -The percent change in total-C from baseline to week 12. -The proportion of patients reaching LDL-C goal at week 24 -The percent change in Lp(a) from baseline to week 24. -The percent change in HDL-C from baseline to week 24. -The percent change in HDL-C from baseline to week 12. -The percent change in Lp(a) from baseline to week 12. -The percent change in fasting TG from baseline to week 24. -The percent change in fasting TG from baseline to week 12. -The percent change in ApoA-1 from baseline to week 24. -The percent change in ApoA-1 from baseline to week 12. |
variaz.% del C-LDL dal basale alla sett.12;variaz.% dei valori di ApoB dal basale alla sett.24;variaz.% dei valori del C-non-HDL dal basale alla sett.24;variaz.% dei valori del C-totale dal basale alla sett.24;variaz.% dei valori di ApoB dal basale alla sett.12;variaz.% dei valori del C-non-HDL dal basale alla sett.12;variaz.% dei valori del C- totale dal basale alla sett.12;proporzione di pazienti che raggiunge valori di C-LDL previsti alla sett.24;variaz.% dei valori di Lp(a) dal basale alla sett.24;variaz.% dei valori del C-HDL dal basale alle sett.12 e 24;variaz.% dei valori di Lp(a) dal basale alla sett.12;variaz.% dei valori di TG a digiuno dal basale alle sett.12 e 24;variaz.% dei valori di ApoA-1 dal basale alle sett. 12 e 24 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to week 12 or week 24 |
Dal baseline alla settimana 12 o 24. |
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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 | No |
E.6.11 | Pharmacogenomic | Yes |
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 |
Comparatore attivo |
Active-comparator |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 7 |
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 | 7 |
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 |
Australia |
Brazil |
Canada |
Mexico |
New Zealand |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 16 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 16 |
E.8.9.2 | In all countries concerned by the trial days | 0 |