| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Dyslipidemia |
| Dislipidemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Abnormal amounts of lipids in the blood |
| Livelli anormali di grassi nel sangue |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058108 |
| E.1.2 | Term | Dyslipidaemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 effect of evolocumab on fibrous cap thickness (FCT) in subjects with non ST elevation acute coronary syndrome (NSTE ACS) who are taking maximally tolerated statin therapy. |
| Valutare l’effetto di evolocumab sullo spessore del cappuccio fibroso (FCT) in soggetti affetti da sindrome coronarica acuta senza sopraslivellamento del tratto ST (NSTE-ACS), in terapia con statine alla massima dose tollerata. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the effects of evolocumab on coronary plaque morphology in subjects with NSTE-ACS who are taking maximally tolerated statin therapy.
-Safety: to evaluate the safety and tolerability of evolocumab treatment in subjects with NSTE-ACS who are taking maximally tolerated statin therapy.
-Exploratory:
•To evaluate the effects of evolocumab on lipid parameters in subjects with NSTE ACS who are taking maximally tolerated statin therapy.
•To evaluate the effects of evolocumab on features of coronary plaques in subjects with NSTE ACS who are taking maximally tolerated statin therapy using different imaging techniques.
|
Valutare gli effetti di evolocumab sulla morfologia delle placche coronariche in soggetti affetti da NSTE-ACS, in terapia con statine alla massima dose tollerata.
SAFETY:
Valutare la sicurezza e la tollerabilità del trattamento con evolocumab in soggetti con NSTE-ACS in terapia con statine alla massima dose tollerata.
ESPLORATORI:
Valutare gli effetti di evolocumab sui parametri lipidici in soggetti con NSTE-ACS in terapia con statine alla massima dose tollerata. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Key Inclusion Criteria
•Age = 18 years at screening.
•Clinical indication for coronary angiography during admission due to NSTE-ACS with interventional treatment of culprit plaque.
•LDL-C level via local lab assessment based on statin use at screening:
- No statin use: = 130 mg/dL
- Low- or moderate-intensity statin use: = 80 mg/dL
- High-intensity statin use: = 60 mg/dL
•On maximally tolerated statin therapy in accordance with standard of care per local guidelines prior to randomization.
•Tolerates placebo run-in injection at screening.
•Meet all the following criteria at the qualifying coronary angiogram:
- Angiographic evidence of coronary artery disease (CAD) with = 20% reduction of lumen diameter by angiographic visual estimation, in addition to the culprit plaque.
- Left main coronary artery must not have a > 50% reduction in lumen diameter by visual angiographic estimation.
- Targeted vessel:
-may not be the culprit vessel for the current or a previous myocardial infarction (MI).
-has not undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and may not be a bypass graft.
-may not be a candidate for PCI or CABG currently or over the next 12 months, in the opinion of the investigator.
-must be accessible by the OCT catheter.
- Targeted segment:
-must have up to 50% but not > 50% reduction in lumen diameter by visual angiographic estimation and must be at least 40 mm in length.
-must contain at least 1 image with an FCT of = 120 µm and at least 1 image with a lipid arc of > 90° as determined by the imaging core laboratory.
-distal plaques of up to 50% stenosis by visual angiographic estimation are permitted, provided that such stenosis is not a target for PCI or CABG.
|
Principali criteri di inclusione
• Età = 18 anni al momento dello screening
• Indicazione clinica all’angiografia coronarica durante ricovero per NSTE-ACS, con trattamento interventistico della placca responsabile.
• Livello di C-LDL valutato dal laboratorio locale in base all’uso di statine allo screening:
• Nessuna dose di statine: =130 mg/dL
• Uso di statine a bassa o moderata intensità: =80 mg/dL
• Uso di statine ad alta intensità: =60 mg/dL
• In terapia con statine alla massima dose tollerata, conformemente agli standard terapeutici stabiliti dalle linee guida locali, prima della randomizzazione.
• Tollera l’iniezione di run-in con placebo, effettuata allo screening.
• Soddisfa tutti i seguenti criteri all’angiocoronarografia qualificante:
• Evidenza angiografica di coronaropatia (CAD) con riduzione del diametro del lume = 20% alla stima visiva su angiografia, in aggiunta alla placca responsabile.
• L’arteria coronaria principale sinistra non deve presentare una riduzione del diametro del lume > 50% alla stima visiva su angiografia.
• Vaso target:
• non può essere il vaso responsabile per l’attuale o un pregresso infarto miocardico (IM).
• non è stato sottoposto a precedente intervento coronarico percutaneo (PCI), o innesto di bypass aortocoronarico (CABG), e non può essere un innesto di bypass.
• secondo il giudizio dello sperimentatore, non può essere, né attualmente, né nel corso dei 12 mesi successivi, un candidato per PCI o CAGB.
• deve essere accessibile con catetere OCT.
• Segmento target:
• deve presentare una riduzione fino, ma non superiore, al 50% del diametro del lume, alla stima visiva su angiografia, e non essere di lunghezza inferiore a 40 mm.
• deve contenere almeno 1 immagine con uno spessore del cappuccio fibroso = 120 µm, e almeno 1 immagine con un arco lipidico > 90°, come stabilito dal laboratorio di imaging rincipale.
• sono consentite placche distali con stenosi fino al 50% alla stima visiva su angiografia, a condizione che detta stenosi non sia target di PCI o CAGB. |
|
| E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria apply.
•Disease Related:
-ST-segment elevation myocardial infarction (STEMI) or left bundle branch block (LBBB).
-ACS likely to be caused by a non-atherosclerotic process, in the opinion of the investigator (ie, type 2 myocardial infarction, which is characterized by an imbalance between myocardial oxygen demand and supply).
-Clinically significant heart disease which in the opinion of the investigator is likely to require coronary bypass surgery, PCI (does not apply to PCI of non STEMI (NSTEMI) during initial screening angiogram), surgical or percutaneous valve repair and/or replacement during the course of the study.
-Any cardiac surgery within 6 weeks prior to screening.
•Diagnostic Assessments
-Triglycerides = 400 mg/dL (4.5 mmol/L) at screening.
-Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening.
•Other Medical Conditions
-Malignancy except non-melanoma skin cancers, cervical, or breast ductal carcinoma in situ within the last 5 years.
-Intolerant to statins as determined by principal investigator.
Prior/Concomitant Therapy
-Previously received or receiving evolocumab or any other therapy to inhibit PCSK9.
-Previously received a cholesterol ester transfer protein (CETP) inhibitor (ie, anacetrapib, dalcetrapib, evacetrapib), mipomersen, lomitapide, or has undergone LDL apheresis in the last 12 months prior to LDL-C screening.
•Prior/Concurrent Clinical Study Experience
-Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.
•Other Exclusions
-Baseline OCT does not meet OCT imaging criteria as determined by the imagine core laboratory technical standards.
-Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 15 weeks after the last dose of investigational product. (Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test.)
-Female subjects of childbearing potential unwilling to use 1 acceptable method of effective contraception during treatment and for an additional 15 weeks after the last dose of investigational product. Refer to Appendix 5 for additional contraceptive information.
-Female subject who has not used an acceptable method(s) of birth control for at least 1 month prior to screening, unless the female subject is sterilized or postmenopausal.
-Known sensitivity to any of the products or components (eg, carboxymethylcellulose) to be administered during dosing.
-Not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject’s and investigator’s knowledge.
-Unreliability based on the investigator's (or designee’s) knowledge (eg, alcohol or other drug abuse, inability or unwillingness to adhere to the protocol, or psychosis).
-History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
|
I soggetti sono esclusi dallo studio se si applica uno dei seguenti criteri.
• correlati alle malattie:
-Infarto miocardico con innalzamento del tratto ST (STEMI) o blocco di branca sinistro (LBBB).
-ACS che può essere causato da un processo non aterosclerotico, secondo il parere dello sperimentatore (cioè infarto miocardico di tipo 2, che è caratterizzato da uno squilibrio tra domanda e offerta di ossigeno miocardico).
-Sufficienza cardiaca clinicamente significativa che secondo il parere dello sperimentatore richiede probabilmente un intervento chirurgico di bypass coronarico, PCI (non si applica al PCI non-STEMI (NSTEMI) durante l'angiogramma iniziale di screening), riparazione o sostituzione della valvola chirurgica o percutanea durante il corso dello studio.
-Qualsiasi intervento cardiaco nelle 6 settimane prima dello screening.
• Valutazioni diagnostiche
-Trigliceridi = 400 mg / dl (4,5 mmol / l) allo screening.
- disfunzione renale da grave a moderata, definita come una velocità di filtrazione glomerulare stimata (eGFR) <30 ml / min / 1,73m2 allo screening.
• Altre condizioni mediche
-Malignità, tranne tumori della pelle non melanoma, carcinoma cervicale o del dotto mammario in situ negli ultimi 5 anni.
-Intollerante alle statine come determinato dallo sperimentatore.
Terapie precedenti / concomitanti
- ha ricevuto o riceve evolocumab o qualsiasi altra terapia inibitore del PCSK9.
-Precedentemente ha ricevuto un inibitore della proteina di trasferimento dell'estere del colesterolo (CETP) (cioè, anacetrapib, dalcetrapib, evacetrapib), mipomersen, lomitapide o è stato sottoposto ad aferesi LDL negli ultimi 12 mesi prima dello screening LDL-C.
• Esperienza precedente / concomitante in studi clinici
- attualmente in trattamento con un altro dispositivo o farmaco sperimentale, o siano trascorsi meno di 30 giorni dal termine del trattamento con un altro dispositivo o farmaco sperimentale. Sono escluse altre procedure investigative durante la partecipazione a questo studio.
• Altre esclusioni
- L'OCT di base non soddisfa i criteri di imaging OCT come determinato dagli standard tecnici di laboratorio.
-Soggetti femminili in stato di gravidanza o allattamento al seno o sta pianificando una gravidanza o allattamento al seno durante il trattamento e per ulteriori 15 settimane dopo l'ultima dose di prodotto sperimentale. (Le donne in età fertile devono essere incluse nello studio solo dopo un periodo mestruale confermato e un test di gravidanza o di siero negativo altamente sensibile).
- Soggetti femminili potenzialmente fertili che non vogliono usare 1 metodo accettabile di contraccezione efficace durante il trattamento e per ulteriori 15 settimane dopo l'ultima dose di prodotto sperimentale. Fare riferimento all'Appendice 5 per ulteriori informazioni sulla contraccezione.
- Soggetti femminili che non hanno utilizzato un metodo/i di controllo delle nascite accettabile per almeno 1 mese prima dello screening, a meno che il soggetto femminile non sia sterilizzato o in postmenopausa.
-Sensibilità nota a qualsiasi prodotto o componente (ad es. Carbossimetilcellulosa) da somministrare durante lo studio.
-Non essere disponibile per completare tutte le visite o le procedure di studio richieste dal protocollo e / o rispettare tutte le procedure di studio richieste al meglio delle conoscenze del soggetto e dello sperimentatore.
- Inaffidabilità basata sulla conoscenza dello sperimentatore (o designato) (ad esempio, abuso di alcool o di altre droghe, incapacità o mancanza di volontà di aderire al protocollo o psicosi).
-Storia o evidenza di qualsiasi altro disturbo, condizione o malattia clinicamente significativa (ad eccezione di quelli descritti sopra) che, secondo il parere dello sperimentatore o del medico Amgen, se consultato, potrebbero rappresentare un rischio per la sicurezza dei soggetti o interferire con la valutazione, le procedure o il completamento dello studio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Absolute change in minimum fibrous cap thickness (FCT) in a matched segment of artery as determined by optical coherence tomography (OCT) from baseline to week 50. |
| Variazione assoluta dello spessore minimo del cappuccio fibroso in uno stesso segmento arterioso, determinata mediante tomografia a coerenza ottica (OCT) dal basale alla settimana 50. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
OCT: at screening and week 50 ± 2 week
|
| OCT: allo screening e alla settimana 50 ± 2 |
|
| E.5.2 | Secondary end point(s) |
1. Coronary artery segment-based:
- Percent change in minimum FCT in a matched segment of artery as
determined by OCT from baseline to week 50.
- Absolute change in mean minimum FCT for all images assessed in an individual subject as determined by OCT from baseline to week 50.
- Absolute change in the maximum lipid arc in a matched segment of artery as determined by OCT from baseline to week 50.
2. Plaque-based: Absolute change in minimum FCT, maximum lipid arc, and lipid core length in lipid rich plaques defined as minimum FCT < 120 µm and lipid arc > 90° in at least 3 consecutive images as determined by OCT from baseline to week 50.
3. Safety: Subject incidence of treatment-emergent adverse events
and serious adverse events.
4. Exploratory:
-Absolute and percent changes in lipid parameters by visit from baseline.
-Absolute change in number of microchannels in matched segments of all lesions assessed in an individual subject as determined by OCT from baseline to week 50.
-Absolute change in macrophage composition in matched segments of all lesions assessed in an individual subject as determined by OCT from baseline to week 50.
-Absolute change in lipid content in matched segments of all lesions assessed in an individual subject as determined by IVUS from baseline to week 50.
|
In base al segmento dell’arteria coronaria:
• Variazione percentuale dello spessore minimo del cappuccio fibroso in uno stesso segmento arterioso, determinata mediante OCT dal basale alla settimana 50.
• Variazione assoluta dello spessore minimo medio del cappuccio fibroso in tutte le immagini valutate per un singolo soggetto, determinata mediante OCT dal basale alla settimana 50.
• Variazione assoluta dell’arco lipidico massimo in uno stesso segmento arterioso, determinata mediante OCT dal basale alla settimana 50.
In base alla placca:
• Variazione assoluta dello spessore minimo del cappuccio fibroso, dell’arco lipidico massimo e della lunghezza del core lipidico delle placche ad alto contenuto lipidico, definite da uno spessore minimo del cappuccio fibroso < 120 µm e un arco lipidico > 90°, in almeno 3 immagini consecutive, determinata mediante OCT dal basale alla settimana 50. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OCT: at screening and week 50 ± 2 week.
IVUS: at screening and week 50 ± 2 week.
Adverse events and serious adverse events: at screening, day 1, week 4, 12, 24, 36, 50 and 52.
Lipid testing: at screening.
Fasting lipid testing: at day 1, week 24 and week 50. |
OCT: allo screening e alla settimana 50 ± 2 .
IVUS:allo screening e alla settimana 50 ± 2 .
Adverse events e serious adverse events: allo screening, giorno 1, settimane 4, 12, 24, 36, 50 e 52.
Test lipidi: allo screening
test lipidi a digiuno: al giorno 1, settimana 24 e settimana 50. |
|
| 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 | No |
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 | Information not present in EudraCT |
| 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 |
| Japan |
| South Africa |
| United States |
|
| 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
|
LVLS
|
| Ultima visita dell'ultimo soggetto |
|
| 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 | 11 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
Print
