| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Atherosclerotic cardiovascular disease |
| Malattia aterosclerotica cardiovascolare |
|
| E.1.1.1 | Medical condition in easily understood language |
| Atherosclerotic cardiovascular disease |
| Malattia aterosclerotica cardiovascolare |
|
| 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 | 10051615 |
| E.1.2 | Term | Atherosclerotic cardiovascular disease |
| E.1.2 | System Organ Class | 10047065 - Vascular 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 |
| The primary objective is to assess the effect of lipid modification using anacetrapib 100mg daily versus placebo on the time to first ''Major Coronary Event''(defined as the occurrence of coronary death, myocardial infarction or coronary revascularization procedure) during the scheduled treatment period. |
| L’obiettivo principale dello studio è valutare l'effetto della modificazione dei valori ematici dei lipidi, ottenuta attraverso la somministrazione di anacetrapib 100mg versus placebo, sui tempi di insorgenza di ''eventi coronarici maggiori'' (definiti come morte coronarica, infarto miocardico o rivascolarizzazione coronarica) durante il periodo di trattamento previsto. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objective include assessment of the effects of allocation to anacetrapib versus placebo on: i) coronary death or myocardial infarction (key secondary objective); ii) coronary revascularization procedure; iii) Presumed ischaemic stroke (i.e. not known to be haemorrhagic); and iv) Death from all cardiovascular causes |
| Gli obiettivi secondari includono la valutazione degli effetti della somministrazione di anacetrapib versus placebo su: i) morte coronarica o infarto miocardico (obiettivi secondari principali); ii) procedure di rivascolarizzazione coronarica; iii) presunto ictus ischemico (i.e. di cui non si sia a conoscenza se sia emorragico); e iv) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Patients must be aged at least 50 at the time of initial invitation, and at least one of the following inclusion criteria must be satisfied: •History of MI; or •Cerebrovascular atherosclerotic disease (i.e. history of presumed ischaemic stroke or carotid revascularization); or •Peripheral arterial disease (i.e. history of non-coronary revascularization, including aortic aneurysm repair or graft); or • Diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. treatment or hospitalization for angina, or a history of coronary revascularization or acute coronary syndrome). |
| Età ≥50 anni al momento dell'invito ed almeno una delle seguenti condizioni: •Pregresso IMA; •Vasculopatia cerebrale aterosclerotica (i.e. storia di ictus ischemico o presunto ischemico, rivascolarizzazione carotidea); •Vasculopatia periferica (i.e. rivascolarizzazione periferica, intervento per aneurisma dell’aorta); •Diabete mellito con evidenza di cardiopatia ischemica (i.e. terapia o ricoveri per angina, storia di rivascolarizzazione coronarica o di sindrome coronarica acuta). |
|
| E.4 | Principal exclusion criteria |
| None of the following must be satisfied: • Acute MI, acute coronary syndrome or stroke within 4 weeks prior to Screening Visit or during Run-in (but such individuals may be entered later, if appropriate); • Planned coronary revascularization procedure within the next 6 months (such individuals may be entered later, if appropriate); • Definite history of chronic liver disease, or abnormal liver function (i.e. ALT >2x ULN). Note: Individuals with a history of acute hepatitis are eligible provided this ALT limit is not exceeded; • Severe renal insufficiency (i.e. creatinine >200 µmol/L [2.3 mg/dL], dialysis or functioning renal transplant); • Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or CK >3x ULN; • Previous significant adverse reaction to a statin or anacetrapib; • Current treatment with any of the following lipid-lowering treatments: (i) a regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily; or (ii) fibric acid derivative (“fibrate”, including gemfibrozil); or (iii) niacin (nicotinic acid) at doses above 100 mg daily • Concurrent treatment with a medication that is contraindicated with anacetrapib or atorvastatin: (i) any potent CYP3A4 inhibitor, such as: (a) macrolide antibiotics (erythromycin, clarithromycin, telithromycin); (b) daptomycin (c) systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole); (d) protease inhibitors (e.g. atazanavir); (e) nefazodone (ii) ciclosporin (iii) systemic use of fusidic acid Note: Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate; • Known to be poorly compliant with clinic visits or prescribed medication; • Medical history that might limit the individual’s ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; history of cancer or evidence of spread within last 5 years, other than non-melanoma skin cancer; or recent history of alcohol or substance misuse); • Women of child-bearing potential (unless using adequate contraception); • Current participation in a clinical trial with an unlicensed drug or device. Individuals will also be excluded at the Screening visit if it is considered unlikely that they will achieve total cholesterol <3.5 mmol/L (135 mg/dL) on the highest atorvastatin dose (80 mg daily). In addition, individuals will be excluded at the Randomization visit if any of the following are true: • Total cholesterol above 4 mmol/L • Non-compliant with run-in treatment (<90% scheduled run-in medication taken) • Individual is no longer willing to be randomized into the 4-5 year trial • The individual’s doctor is of the view that their patient should not be randomized. |
| Nessuna delle seguenti deve essere presente: •Infarto miocardico, sindrome coronarica acuta o ictus occorsi nelle 4 settimane precedenti la visita di screening o durante il run-in (questi pazienti possono essere rivalutati per l’inclusione successivamente); •Procedure di rivascolarizzazione coronarica programmate nei 6 mesi successivi (questi pazienti possono essere rivalutati per l’inclusione successivamente); •Storia di epatopatia cronica o alterazione dei parametri di funzionalità epatica (i.e. ALT >2 volte il limite superiore di normalità) Nota: possono essere inclusi pazienti con storia di epatite acuta se il valore di ALT rispetta i limiti segnalati; •Insufficienza renale (i.e. creatinina >2.3 mg/dL, trattamento dialitico o trapianto renale); •Presenza di malattie infiammatorie muscolari (es. dermatomiosite, polimiosite), o valori di CK >3 volte il limite superiore di normalità; •Precedenti reazioni avverse alle statine o all’anacetrapib; •Terapia ipolipemizzante con uno dei seguenti regimi farmacologici: qualsiasi trattamento che possa determinare una riduzione del colesterolo LDL superiore rispetto a quella attesa dalla somministrazione di atorvastatina 80 mg/die o fibrati (compreso il gemfibrozil); o niacina (acido nicotinico) con dosi superiori a 100 mg/die •Terapia con farmaci la cui assunzione è controindicata contemporaneamente ad anacetrapib o atorvastatina: Inibitori del CYP3A4 come: - macrolidi (eritromicina, claritromicina, azitromicina, telitromicina); - daptomicina; - imidazolo o altri antimicotici somministrati per via sistemica; - inibitori delle proteasi (es. atazanavir); - nefazodone; Ciclosporina; Acido fusidico somministrato per via sistemica. Nota: tutti i pazienti che assumono uno di questi farmaci temporaneamente possono essere rivalutati al momento in cui interrompono l’assunzione; •Scarsa compliance del paziente sia rispetto alle visite che rispetto alla terapia; •Condizioni che possono limitare la possibilità del paziente a portare a termine lo studio o ad assumere i trattamenti in studio (es. presenza di neoplasie maligne, insufficienza respiratoria grave, abuso di alcool); •Donne in età fertile (a meno di adeguata contraccezione); •Partecipazione in altri studi clinici di trattamento. Se alla visita di screening il medico ritiene che il paziente non abbia probabilità di raggiungere livelli di colesterolo totale <135 mg/dL, neppure con il dosaggio di 80 mg/die di atorvastatina, dovrà escludere il paziente. Inoltre, saranno esclusi i pazienti che, al momento della visita di randomizzazione, presenteranno una delle seguenti condizioni: •Colesterolo totale >155 mg/dL; •Scarsa compliance rispetto al trattamento assegnato nella fase di run-in (<90% di farmaco assunto); •Volontà del paziente a non intraprendere uno studio della durata di 4-5 anni; •Parere contrario alla partecipazione da parte del medico curante. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Major coronary events (defined as the occurrence of coronary death, myocardial infarction or coronary revascularization procedure) during the scheduled treatment period. |
| Evento coronarico maggiore (definito come morte per cause coronariche, infarto miocardico o rivascolarizzazione coronarica). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At least 4 years, and until at least 1900 participants have had an unrefuted major coronary event (primary endpoint) plus at least 950 participants have had a coronary death or myocardial infarction (key secondary endpoint). |
| Almeno 4 anni di follow-up e fino a che 1900 pazienti saranno andati incontro ad un evento coronarico maggiore (endpoint primario) e in almeno 950 pazienti sarà registrata una morte per cause coronariche o un infarto miocardico (endpoint secondari chiave) |
|
| E.5.2 | Secondary end point(s) |
| (i) Coronary death or myocardial infarction (key secondary outcome); (ii) Coronary revascularization procedure; (iii) Presumed ischaemic stroke (i.e. not known to be haemorrhagic); and (iv) Death from all cardiovascular causes. |
| i) Morte coronarica o infarto miocardico ii) rivascolarizzazione coronarica iii) ictus di presunta origine ischemica (i.e. esclusi gli ictus dovuti a emorragia) iv)morte per causa cardiovascolare |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At least 4 years, and until at least 1900 participants have had an unrefuted major coronary event (primary endpoint) plus at least 950 participants have had a coronary death or myocardial infarction (key secondary endpoint). |
| Almeno 4 anni di follow-up e fino a che 1900 pazienti saranno andati incontro ad un evento coronarico maggiore (endpoint primario) e in almeno 950 pazienti sarà registrata una morte per cause coronariche o un infarto miocardico (endpoint secondari chiave) |
|
| 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 | 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 | 33 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 190 |
| 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 |
| Canada |
| China |
| United States |
|
| 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
|
| Median follow-up of at least 4 years and a minimum of 1900 participants have had at least 1 unrefuted major coronary event (primary endpoint) and a minimum of 950 participants have had at least 1 unrefuted coronary death or MI (key secondary endpoint). |
| Follow up medio di 4 anni e almeno 1900 paz. avranno avuto un evento coronarico maggiore (endpoint primario)e almeno 950 paz saranno deceduti per morte coronarica o avranno avuto un infarto miocardico (endpoint secondario). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
| 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 |
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