| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation |
| prevenzione dell'ictus e dell'embolia sistemica in pazienti con fibrillazione atriale non valvolare |
|
| 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 | HLT |
| E.1.2 | Classification code | 10000032 |
| E.1.2 | Term | Cardiac conduction disorders |
| E.1.2 | System Organ Class | 100000004849 |
|
| 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 demonstrate that the efficacy and safety of two blinded doses (110 and 150 mg bid) of dabigatran etexilate in patients with non valvular atrial fibrillation are non inferior to warfarin treatment for the prevention of stroke and systemic embolism |
| dimostrare che la efficacia e la tollerabilita' di dabigatran somministrato ai dosaggi 110 mg e 150 mg bid non sono inferiori a quelli di Warfarin nella prevenzione di ictus ed embolia sistemica nei pazienti con fibrillazione atriale non valvolare |
|
| E.2.2 | Secondary objectives of the trial |
| Incidence of stroke (including hemorrhagic), systemic embolism, all death. Incidence of stroke (including hemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, or vascular deaths (includes deaths from bleeding). |
| studiare l'incidenza di ictus(inclusi ictus emorragici),embolia sistemica e morte; studiare l'incidenza di ictus(inclusi ictus emorragici),embolia sistemica,embolia polmonare,infarto miocardico acuto o morte per cause vascolari (incluse morti per sanguinamenti) |
|
| 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 |
PHARMACOKINETIC/PHARMACODYNAMIC:
Vers:
Date:
Title:
Objectives:
|
FARMACOCINETICA/FARMACODINAMICA:
Vers:
Data:
Titolo:
Obiettivi:
|
|
| E.3 | Principal inclusion criteria |
| 1.) AF documented as follows: a. There is ECG documented AF on the day of screening or randomization b. The patient has had a symptomatic episode of paroxysmal or persistent AF documented by 12 lead ECG within six months prior to randomization c. There is documentation of symptomatic or asymptomatic paroxysmal or persistent AF on two separate occasions, at least one day apart, one of which is within six months prior to randomization. In this case, AF may be documented by 12 lead ECG, rhythm strip, pacemaker/ICD electrogram, or Holter ECG. The duration of AF should be at least 30 seconds. Electrograms (not marker channels or mode switch episodes) from pacemakers and defibrillators can be used to document only one episode of paroxysmal or persistent AF 2.) In addition to documented AF, patients must have one of the following additional risk factors for stroke: a. History of previous stroke, transient ischemic attack, or systemic embolism b. Left ventricular ejection fraction <40% documented by echocardiogram, radionuclide or contrast angiogram c. Symptomatic heart failure, documented to be NYHA Class 2 or greater d. Age ≥ 75 years e. Age ≥ 65 years and one of the following additional risk factors: i) diabetes mellitus on treatment ii) documented coronary artery disease (any of: prior MI, positive stress exercise test, positive nuclear perfusion study, prior CABG surgery or PCI, angiogram showing ≥75% stenosis in a major coronary artery iii) hypertension requiring medical treatment 3.) Age ≥18 years at entry 4.) Written, informed consent. |
| - Fibrillazione atriale (FA) documentata da: - ECG eseguito il giorno dello screening o della randomizzazione - Episodio sintomatico di FA parossistica o persistente documentata da ECG nei 6 mesi precedenti la randomizzazione - Due episodi distinti di FA parossistica o persistente sintomatica o asintomatica, separati da almeno un giorno, uno dei quali accaduto nei 6 mesi precedenti la randomizzazione. In questo caso la FA puo' essere documentata da ECG a 12 derivazioni, striscia di ritmo, pacemaker/defibrillatore cardioverter impiantabile elettrogramma o Holter ECG. La durata di FA dovra' essere di almeno 30 secondi. Gli elettrogrammi da pacemaker e defibrillatori possono essere utilizzati per documentare uno solo degli episodi di FA parossistica o persistente. - Presenza di almeno uno dei seguenti fattori addizionali di rischio di ictus - Anamnesi positiva per ictus, TIA o embolia sistemica precedente - Frazione di eiezione ventricolare sinistra < 40% documentata da ecocardiogramma, angiogramma con mezzo radioattivo o di contrasto - Scompenso cardiaco sintomatico, classe NYHA > 2 - Eta' > 75 anni - Eta' > 65 anni e presenza di uno dei seguenti fattori di rischio - Diabete mellito in trattamento - Malattia coronarica documentata (per es. precedente IM, test da sforzo positivo, studio di perfusione nucleare positivo, precedente intervento di by-pass aorto-coronarico o rivascolarizzazione coronarica percutanea, angiogramma che mostra stenosi > 75% in una coronaria maggiore) - Ipertensione in trattamento farmacologico - Eta'  18 anni; - Consenso informato scritto |
|
| E.4 | Principal exclusion criteria |
| 1.) History of heart valve disorders (i.e., prosthetic valve or hemodynamically relevant valve disease) 2.) Severe, disabling stroke within the previous 6 months, or any stroke within the previous 14 days 3.) Conditions associated with an increased risk of bleeding: a. Major surgery in the previous month b. Planned surgery or intervention in the next 3 months c. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding d. Gastrointestinal haemorrhage within the past year e. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days f. Hemorrhagic disorder or bleeding diathesis g. Need for anticoagulant treatment for disorders other than atrial fibrillation h. Fibrinolytic agents within 48 hours of study entry i. Uncontrolled hypertension (SBP >180 mmHg and/or DBP >100 mmHg) j. Recent malignancy or radiation therapy (≤6 months) and not expected to survive 3 years Boehringer Ingelheim Pharma GmbH & Co. KG Final 12 Sept2005 BI Trial No.: 1160.26 Page 30 of 114 4.) Contraindication to warfarin treatment 5.) Reversible causes of atrial fibrillation (e.g., cardiac surgery, pulmonary embolism, untreated hyperthyroidism). 6.) Plan to perform a pulmonary vein ablation or surgery for cure of the AF 7.) Severe renal impairment (estimated creatinine clearance ≤30 mL/min) 8.) Active infective endocarditis 9.) Active liver disease, including but not limited to a. Persistent ALT, AST, Alk. Phos. >2 x ULN b. Known active hepatitis C* (as evidenced by positive HCV RNA by sensitive PCR-based assay, such as Roche Monitor or Bayer TMA assay) c. Active hepatitis B* (HBs antigen +, anti HBc IgM+) d. Active hepatitis A 10.) Women who are pregnant or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study (NOTE: A negative pregnancy test must be obtained for any woman of childbearing potential prior to entry into the study) 11.) Anaemia (haemoglobin <100g/L) or thrombocytopenia (platelet count <100 x 109/L) 12.) Patients who have developed transaminase elevations upon exposure to ximelagatran. 13.) Patients who have received an investigational drug in the past 30 days 14.) Patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, has a life expectancy less than the expected duration of the trial due to concomitant disease, or has any condition which in the opinion of the investigator, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse). |
| - Storia di disordini delle valvole cardiache (per es. protesi valvolare o malattia valvolare emodinamicamente rilevante); - Ictus severo, disabilitante nei 6 mesi precedenti oppure qualsiasi tipo di ictus nei 14 giorni precedenti; - Condizioni associate a un aumentato rischio di sanguinamento: - Interventi chirurgici maggiori nel mese precedente - Programmazione di un intervento chirurgico nei 3 mesi successivi - Storia di sanguinamento intracranico, intraoculare, spinale, retroperitoneale o intrarticolare non traumatico - Emorragia gastrointestinale nell'ultimo anno - Ulcera gastroduodenale sintomatica o documentata endoscopicamente negli ultimi 30 giorni - Disordini emorragici o diatesi emorragica - Necessita' di terapia anticoagulante per disordini diversi dalla fibrillazione atriale - Fibrinolisi nelle 48 ore precedenti l'arruolamento - Ipertensione non controllata (PAS > 180 mmHg e/o PAD > 100 mmHg) - Recente neoplasia o terapia radiante (< 6 mesi) e una aspettativa di vita inferiore ai 3 anni - Controindicazioni al trattamento con warfarin - Cause reversibili di fibrillazione atriale (per es. intervento chirurgico cardiaco, embolia polmonare, ipertiroidismo non in trattamento) - Intervento programmato di ablazione della vena polmonare o intervento chirurgico per il trattamento della fibrillazione atriale - Insufficienza renale severa (creatinina clearance < 30 ml/min) - Endocardite infettiva attiva - Malattia epatica attiva, incluso ma non limitato a : - Persistenti valori di ALT, AST e fosfatasi alcalina > 2 volte il limite superiore di normalita' - Epatite C attiva (evidenziata da test positivo per HCV RNA) - Epatite B attiva (HBs antigene +, anti HBc IgM +) - Epatite A attiva (pazienti con anamnesi positiva per epatite B o C dovranno eseguire i test sierologici per epatite B e C prima dell'arruolamento) - Donne in gravidanza o in eta' fertile che rifiutano l'uso di un metodo contraccettivo clinicamente riconosciuto per l'intera durata dello studio (NB all'arruolamento il test di gravidanza dovra' essere negativo per le donne in eta' fertile) - Anemia (emoglobina < 100 g/l) o trombocitopenia (piastrine < 100 x109/l) - Pazienti che hanno avuto un innalzamento delle transaminasi dopo trattamento con ximelagatran - Pazienti che hanno assunto un farmaco sperimentale negli ultimi 30 giorni - Pazienti considerati inaffidabili dallo sperimentatore a seguire le procedure dello studio e la somminsitarzione del farmaco, pazienti con aspettativa di vita inferiore alla durata dello studio a causa di malattie concomitanti, pazienti le cui condizioni controindicano la loro partecipazione allo studio (per es. tossicodipendenza, alcolismo). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy:Incidence of all stroke (including hemorrhagic) or systemic embolism. Safety: • Bleeding events • Major bleeds • Minor bleeds • Hepatobiliary events including clinically relevant changes in liver function tests and hepatic dysfunction • Other adverse events |
| Efficacia: incidenza di ictus(inclusi quelli emorragici) o embolia sistemica. Sicurezza: • Sanguinamenti • Maggiori • Minori • Eventi epatobiliari incluse variazioni clinicamente significativi negli esami per la funzionalita' epatica e la disfunzione epatica. Altri eventi avversi |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| 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 | 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 | No |
| 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 | No |
| 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 |
| Dabigatran: doppio cieco; warfarin: aperto |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 21 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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