E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Ventricular arrhythmia in patients with implantable cardioverterdefibrillator (ICD) |
Aritmia ventricolare in pazienti con cardioverter defibrillatore impiantabile (ICD) |
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E.1.1.1 | Medical condition in easily understood language |
abnormal heartbeat in patients with defibrillator |
Ritmo cardiaco anormale in pazienti con defibrillatore |
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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 | SOC |
E.1.2 | Classification code | 10007541 |
E.1.2 | Term | Cardiac disorders |
E.1.2 | System Organ Class | 10007541 - Cardiac 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 |
The primary objective of this study is to assess the impact of 75 mg azimilide versus placebo on the occurrence of unplanned (non-elective) cardiovascular hospitalizations, unplanned cardiovascular emergency department visits, or cardiovascular death in patients with an ICD. |
L’obiettivo primario di questo studio è di valutare l’impatto di azimilide da 75 mg rispetto al placebo sull’occorrenza di ospedalizzazioni per episodi acuti cardiovascolari non pianificate (non elettive) o visite al pronto soccorso per episodi acuti cardiovascolari o morte cardiovascolare in pazienti con ICD. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to determine whether treatment with 75 mg azimilide versus placebo in patients with an ICD: • Reduces the occurrence of all-cause shocks, as assessed by prolonging time-to-first event; and • Reduces unplanned physician-office visits that resulted in a change in therapy (reprogramming ICD or change in medication as it relates to ICD findings), as assessed by prolonging time-to-first event. |
Gli obiettivi secondari di questo studio intendono determinare se il trattamento con azimilide da 75 mg rispetto al placebo in pazienti con ICD:•Riduce l’occorrenza di shock per qualsiasi causa,valutata prolungando il tempo che intercorre fino al primo evento; e•Riduce le visite presso lo studio medico non pianificate,risultate in una modifica della terapia (riprogrammazione dell’ICD o modifica della cura in relazione agli esiti dell’ICD),valutata prolungando il tempo che intercorre fino al primo evento. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men or women at least 18 years of age with a left ventricular ejection fraction (LVEF) .minus equal to 40% as determined by echocardiography (ECHO), nuclear scan, left ventriculography, or cardiac magnetic resonance (CMR) imaging within 120 days prior to randomization; 2. Have an ICD implanted that meets the following criteria: a. generates a biphasic waveform discharge; b. stores intracardiac electrograms; c. has both anti-tachycardia pacing and anti-bradycardia pacing capabilities; d. has a minimum of 2 anti-tachycardia detecting zones and a ventricular fibrillation zone; e. has arrhythmia-discriminating algorithms (eg, high rate or sudden onset or rate stability). 3. Patients who had their qualifying event before their first ICD implantation (''New ICD Patient''): must have had a documented episode of spontaneous sustained VT or VF (ventricular arrhythmia .major equal 150 bpm lasting at least 30 seconds or requiring intervention during the sustained VT), or cardiac arrest, or VF during the 42 days preceding their first ICD implantation and be randomized during the 60 days immediately following their OR 4. Patients who had their qualifying event after their first ICD implantation or any subsequent re-implantation (''Existing ICD Patient''): must have had an ICD shock triggered by a spontaneous VT or VF after implantation and be randomized during the 180 days following this shock 5. Must have their ICD programmed in the following manner: a. Antitachycardia pacing must be programmed ''on'' for all patients at the time of randomization (see exception in 4[b]). b. The device will be set for a minimum of 2 attempts of ATP in the lowest detection zone. Every attempt should be made to leave the ATP programmed ''on'' during the study unless, in the Investigator's judgment, it is medically necessary to turn ATP ''off.'' If ATP is turned ''off,'' the reason must be recorded on the eCRF. c. The first shock will be delivered no lower than the lowest successful defibrillation energy at implantation or immediately before randomization. d. Programming of the ventricular tachycardia detection rate (the detection zone in which ATP will be given) should follow the parameters shown below, with adaptation dictated by the patient's clinical condition and the Investigator's judgment (VT = ventricular tachycardia): *If the slowest VT rate is . 150 bpm, then the floor should be 10 bpm less than the VT rate and the ceiling should be 200 bpm *If the slowest VT rate is 151 to 194 bpm, then the floor should be 20 bpm less than the VT rate and the ceiling should be 200 bpm *If the slowest VT rate is . 195 bpm or cardiac arrest with no documented VT rate, then the floor should be Ventricular rate: 175 bpm and the ceiling should be 200 bpm e. For dual chamber devices, at least 1 VT discriminator should be enabled (eg, for dual chamber devices, AV dissociation detection). 5. Women who meet one of the following: a. Women of childbearing potential with a negative serum pregnancy test at screening who are not breast feeding, do not plan to become pregnant during the study, and agree to use one or more approved methods of birth control during the study as judged to be appropriate by the Investigator. Approved methods of birth control are: oral, patch, injectable, or implantable hormonal contraception; intrauterine device; diaphragm plus spermicide; or female condom plus spermicide. Abstinence, partner's use of condoms, and partner's vasectomy are not acceptable methods of contraception. b. Women who have been postmenopausal for at least 1 year (with amenorrhea for at least 1 year) or have had a hysterectomy, bilateral salpingooophorectomy, or tubal ligation at least 6 months prior to signing the informed consent. |
1. Uomini o donne di almeno 18 anni d’età con una frazione di eiezione ventricolare sinistra (LVEF).minore uguale al 40% valutata tramite ecocardiografia (ECHO), scansione nucleare, ventricolografia sinistra o risonanza magnetica cardiaca (CMR) per immagini entro 120 giorni prima della randomizzazione; 2. Avere un ICD impiantato che soddisfi i seguenti criteri: a) generi una scarica di forme d’onda bifasiche; b) registri elettrogrammi intracardiaci; c) abbia sia funzionalità di pacing antitachicardico che di pacing antibradicardico; d) abbia un minimo di 2 zone di rilevamento antitachicardico e una zona di fibrillazione ventricolare; e e) abbia algoritmi discriminanti della tachicardia (ad es. battito elevato o improvvisa insorgenza o stabilità del ritmo). 3. I pazienti sono idonei a partecipare allo studio fermo restando che soddisfino uno dei seguenti 2 criteri: f) I pazienti che hanno riportato l’evento qualificante prima dell’impianto del primo ICD (PAZIENTE CON ICD NUOVO): devono aver riportato un episodio documentato di TV spontanea prolungata (TV maggiore uguale a 150 bpm della durata di almeno 30 secondi o che la TV prolungata abbia reso necessario un intervento), arresto cardiaco, o FV durante i 42 giorni che precedono il primo impianto di ICD ed essere stati randomizzati durante i 60 giorni immediatamente successivi al primo impianto di ICD. o g) I pazienti che hanno riportato l’evento qualificante dopo il primo impianto di ICD o qualsiasi re-impianto successivo (PAZIENTE CON ICD PREESISTENTE): devono aver avuto uno shock da ICD attivato da una TV o una FV spontanea dopo l'impianto ed essere stati randomizzati durante i 180 giorni successivi allo shock. Per gli altri criteri d'inclusione vedere Protocollo. |
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E.4 | Principal exclusion criteria |
1. Have New York Heart Association (NYHA) Class IV CHF or have decompensated CHF at the time of randomization; 2. Have unstable angina pectoris or a myocardial infarction within 30 days of randomization; 3. Have a history of Torsade de Pointes or heart transplantation; 4. Have chronic atrial fibrillation or atrial fibrillation/flutter, that is not adequately rate-controlled in the judgment of the Investigator, at screening; 5. Have an electrocardiogram (ECG) with a QTc value > 460 msec (with a QRS . 120 msec), or a JTc value > 340 msec (with a QRS > 120 msec) (QT and JT intervals corrected by Bazett's formula for heart rate) recorded during screening; 6. Have abnormalities (at screening) in the following clinical laboratory parameters: creatinine > 2.5 mg/dL (221 ƒÊmol/L); serum alanine aminotransferase, aspartate aminotransferase, or gammaglutamyltransferase . 3 E upper limit of normal (ULN), or bilirubin . 2 E ULN; potassium < 4.0 mEq or > 5.5 mEq, or magnesium below the lower limit of normal (potassium and magnesium levels can be adjusted back to normal range if judged by the Investigator, in consultation with the Study Medical Monitor, to be stabilized before randomization); 7. Have an absolute neutrophil count (ANC) < 1000/ƒÊL prior to randomization; 8. Are currently taking systemic Class I or other Class III antiarrhythmic drugs (must be off for . 5 dosing-intervals prior to randomization), including but not limited to quinidine, procainamide, disopyramide, systemic lidocaine, phenytoin, mexiletine, dofetilide, ibutilide, dronedarone, propafenone, moricizine, ranolazine, and sotalol; see exclusion criterion 11 regarding amiodarone; 9. Are currently taking systemic drugs that prolong the QT interval (must be off for 5 half-lives before dosing), including but not limited to clarithromycin, azithromycin, erythromycin, hydroxyzine, phenothiazines, and probucol; 10. Are currently taking or have taken immune-modulating drugs (eg, azathioprine, methotrexate, tumor necrosis factor alpha modifying drugs, or similar drugs which could affect the immune system or white blood cells) within 90 days before randomization; 11. Have taken oral amiodarone within 60 days before randomization or intravenous amiodarone within 14 days before randomization; or if amiodarone treatment (oral or IV) was . 24 hours, have taken it within 5 days before randomization; 12. Use ticlopidine 30 days before randomization; 13. Have uncontrolled or untreated hypertension (systolic > 170 mm Hg, diastolic > 100 mm Hg). If a patient is receiving medical therapy for hypertension, his or her blood pressure should be stable for at least 1 week before randomization; 14. If female, are currently pregnant or breast feeding, or plan to become pregnant during the course of the study; 15. Have neoplasia, immune, infectious, or degenerative diseases that are likely to cause death or significant morbidity during the clinical study; 16. Have a systemic disease that, in the opinion of the Investigator, could impact compliance or study results; 17. Have qualifying ventricular fibrillation (episode that justified ICD implantation) during the acute phase (within 48 hours) of a myocardial infarction; 18. Are taking an investigational new drug, or have participated in any investigational study (with an approved or non-approved drug) within 30 days of randomization; XML File Identifier: 19. Have a non-approved ICD system (lead or generator); For the remaining exclusion criteria, please see the protocol. |
1. Soffrono di insufficienza cardiaca congestizia (CHF) di classe IV secondo la classificazione della New York Heart Association (NYHA) o di CHF scompensata all’atto della randomizzazione; 2. Soffrono di angina pectoris instabile o di infarto miocardico entro 30 giorni dalla randomizzazione; 3. Hanno una storia di Torsade de Pointes o di trapianto cardiaco; 4. Soffrono di fibrillazione atriale cronica o di fibrillazione/flutter atriale, il cui ritmo non è adeguatamente controllato secondo il parere dello sperimentatore, allo screening; 5. Presentano un elettrocardiogramma (ECG) con un valore QTc >460 msec (con un QRS 120 msec), o un valore JTc >340 msec (con un QRS >120 msec) (intervalli QT e JT corretti dalla formula di Bazett per il ritmo cardiaco) registrato durante lo screening; 6. Riportano anomalie (allo screening) nei seguenti parametri di laboratorio clinici: creatinina >2,5 mg/dL (221 ìmol/L); alanina aminotransferasi sierica, aspartato aminotransferasi, o gamma-glutamiltransferasi ≥3 × limite superiore alla norma (ULN), o bilirubina ≥2 × ULN; potassio <4,0 mEq o >5,5 mEq, o magnesio al di sotto del limite inferiore alla norma (i livelli di potassio e magnesio possono essere riportati nella norma se secondo il parere dello sperimentatore, in consulto con il Medico supervisore dello studio, devono essere stabilizzati prima della randomizzazione); 7. Hanno una conta assoluta dei neutrofili (ANC) <1000/ìL prima della randomizzazione; 8. Stanno assumendo farmaci antiaritmici sistemici di Classe I o di Classe III (devono avere interrotto da 5 intervalli di dose prima della randomizzazione), incluso ma in via non limitativa chinidina, procainamide, disopiramide, lidocaina sistemica, fenitoina, mexiletina, dofetilide, ibutilide, dronedarone, propafenone, moricizina, ranolazina, e sotalolo; vedi i criteri di esclusione 11 riguardanti l’amiodarone: 9. Stanno assumendo farmaci sistemici che prolungano l’intervallo QT (devono avere interrotto da 5 emivite prima della somministrazione), incluso ma in via non limitativa claritromicina, azitromicina, eritromicina, idrossizina, fenotiazina e probucolo; 10. Stanno assumendo o hanno assunto farmaci immuno-modulatori (ovvero, azatioprina, metotrexato, farmaci modificatori del fattore di necrosi tumorale alfa, o farmaci analoghi che potrebbero influire sul sistema immunitario o sui globuli bianchi) entro 90 giorni prima della randomizzazione; 11. Hanno assunto amiodarone orale entro 60 giorni prima della randomizzazione o amiodarone endovena entro 14 giorni prima della randomizzazione; o se il trattamento a base di amiodarone (orale o IV) ha avuto luogo ≤ 24 ore, lo hanno assunto entro 5 giorni prima della randomizzazione. 12. Usano ticlopidina 30 giorni prima della randomizzazione; 13. Hanno ipertensione incontrollata o non trattata (sistolica >170 mmHg, diastolica >100 mmHg). Se un paziente riceve terapia medica per l’ipertensione, la sua pressione sanguigna deve essere stabile per almeno 1 settimana prima della randomizzazione; 14. Se donne, incinte o in allattamento, o pianificano una gravidanza durante il corso dello studio; 15. Hanno patologie neoplastiche, immunitarie, infettive o degenerative che potrebbero causare il decesso o morbilità significativa durante lo studio clinico; 16. Hanno una malattia sistemica che, secondo lo sperimentatore, potrebbe avere un impatto sulla conformità o sui risultati dello studio; 17. Hanno FV qualificante (episodio che ha giustificato l’impianto di ICD) durante la fase acuta (entro 48 ore) di un infarto miocardico; 18. Stanno assumendo un nuovo farmaco sperimentale, o hanno partecipato ad uno studio sperimentale (con un farmaco approvato o non approvato) entro 30 giorni dalla randomizzazione; 19. Hanno un sistema di ICD non approvato (piombo o generatore); Per i rimanenti criteri d'esclusione vedere protocollo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the time-to-first-event of unplanned cardiovascular hospitalizations,unplanned cardiovascular emergency department visits,or cardiovascular death. |
L’endpoint di efficacia primario è il tempo che intercorre fino al primo evento di ospedalizzazioni per episodi acuti cardiovascolari non pianificate, visite al pronto soccorso per episodi acuti cardiovascolari non pianificate o morte cardiovascolare. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the purposes of this study, cardiovascular events which trigger unplanned cardiovascular hospitalizations, unplanned cardiovascular emergency department visits are: • arrhythmias, • heart failure, • non-fatal cardiac arrest, • acute coronary syndrome, • cerebrovascular accident (except intracranial hemorrhage), • transient ischemic attack, • cardiovascular lightheadedness, • cardiovascular dizziness, • cardiovascular syncope, and • cardiovascular near-syncope. As part of the adjudication process, the CEC will classify cardiovascular events as arrhythmic or non-arrhythmic. |
Per gli scopi dello studio, gli eventi cardiovascolari che conducono ad ospedalizzazioni per episodi acuti cardiovascolari non pianificate, visite al pronto soccorso per episodi acuti cardiovascolari non pianificate sono:
• aritmie,
• insufficienza cardiaca,
• arresto cardiaco non fatale,
• sindrome coronarica acuta,
• accidente cerebrovascolare (eccetto emorragia intracranica),
• attacco ischemico transitorio,
• stordimento cardiovascolare,
• vertigini cardiovascolari,
• sincope cardiovascolare, e
• episodio sincopale cardiovascolare.
Nell’ambito del processo di aggiudicazione, il CEC classificherà gli eventi cardiovascolari come aritmici o non aritmici. |
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E.5.2 | Secondary end point(s) |
Time-to-first all-cause shock; and Time-to-first unplanned physician-office visits that resulted in a change in therapy (reprogramming ICD or change in medication as it relates to ICD findings). |
Gli endpoint di efficacia secondari sono:
• Tempo che intercorre fino al primo shock di qualsiasi causa; e
• Tempo che intercorre fino alle prime visite presso lo studio medico non pianificate che sono risultate in una modifica della terapia (riprogrammazione dell’ICD o modifica della cura in relazione agli esiti dell’ICD) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
unplanned cardiovascular hospitalization, unplanned cardiovascular emergency room department visit, or cardiovascular death, unscheduled ICD-related physician office visit, or end of study, or withdrawal. |
All’occorrenza di un endpoint di efficacia definito dal protocollo (ospedalizzazione per episodio acuto cardiovascolare non pianificata, visita al pronto soccorso per episodio acuto cardiovascolare non pianificato o morte cardiovascolare), visita non programmata presso lo studio medico in relazione allo ICD, e al termine dello studio o al ritiro. |
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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 | 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) | Yes |
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 | 75 |
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 |
Canada |
Chile |
Israel |
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 | 30 |
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 | 30 |
E.8.9.2 | In all countries concerned by the trial days | 0 |