| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| confirmed venous thromboembolism (VTE)i.e. uni or bilateral deep vein thrombosis (DVT)of the leg involving proximal veins and/or pulmonary embolism (PE)-treated with anticoagulant for 3 to 12 months |
| trombosi venosa profonda (TVP)sintomatica mono- o bilaterale delle vene prossimali della gamba e/o embolia polmonare trattate con terapia anticoagulante per 3-12 mesi |
|
| 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 | HLGT |
| E.1.2 | Classification code | 10014523 |
| E.1.2 | Term | Embolism and thrombosis |
| 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 |
| determine the comparative efficacy of dabigatran etexilate 150 mg bid administered orally and warfarin PRN to maintain an INR of 2.0-3.0 for the long-term treatment and secondary prevention of symptomatic venous thromboembolism in patients who have been successfully treated with standard doses of an approved anticoagulant for 6-36 months for confirmed acute symptomatic VTE. |
| valutare l'efficacia di dabigatran (150 mg b.i.d.) in confronto a warfarin (dosaggio terapeutico INR 2.0-3.0) somministrato dopo una terapia anticoagulante di 6-36 mesi per il trattamento di TEV, nella prevenzione secondaria delle recidive di tromboembolismo venoso sintomatico. |
|
| E.2.2 | Secondary objectives of the trial |
| to determine the comparative safety of dabigatran etexilate (150 mg bid)administered orally and warfarin (to mantain an INR of 2.0-3.0) for the long-term treatment of venous thromboembolism |
| valutare la tollerabilita' di dabigatran etessilato (150 mg bid) in confronto a Warfarin (INR compreso tra 2.0-3.0)nel trattamento a lungo termine del tromboembolismo venoso |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| -objectively confirmed symptomatic uni- or bilateral DVT of the leg involving proximal veins or PE, treated with approved anticoagulant therapy, or with study drug taken during participation in trial 1160.53 or trial 1160.46, for 3 to 12 months at the time of screening, in patients considered at increased risk of recurrent VTE [proximal veins are: trifurcation area, popliteal, superficial femoral, deep femoral, common femoral and iliac vein] -.Male or female, being 18 years of age or older -.Written informed consent for study participation |
| -Trombosi venosa profonda (TVP) mono- o bilaterale, sintomatica delle vene prossimali della gamba (area di triforcazione, vena poplitea, femorale superficiale, femorale profonda, femorale comune ed iliaca) o embolia polmonare confermati da test clinici oggettivi, trattate con terapia anticoagulante in commercio, o con il farmaco in studio assunto durante la partecipazione allo studio 1160.53 o allo studio 1160.46, per 3-12 mesi al momento dello screening, in pazienti con elevato rischio di recidiva di eventi tromboembolici venosi; -maschi o femmine di eta` > 18 anni; -ottenimento del consenso informato scritto |
|
| E.4 | Principal exclusion criteria |
| -Symptomatic DVT or PE at screening -Patients with primary PE with suspected origin other that leg limbs (e.g. upper limbs, right heart). -Actual or anticipated use of vena cava filter -Interruption of anticoagulant therapy for 2 or more weeks during the 3-6 months of treatment for the prior VTE. -Patients who in the investigator's opinion should not be treated with warfarin -Allergy to warfarin or dabigatran, or to one of the excipients included in these medications -Patients who in the investigator's judgement are perceived as having an excessive risk of bleeding, for example because of: -Hemorrhagic disorder or bleeding diathesis -Trauma or major surgery within the last month or as long as an excessive risk of bleeding persists after these events, or planned major surgery -Any of the following intracranial pathologies: neoplasm, arteriovenous malformation or aneurysm -History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding -Gastrointestinal haemorrhage within the past 3 months. -Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days -Treatment with thrombolytic agents within 14 days before enrolment -Anticipated need of restricted medication during the treatment period (see Section 4.2.2) -Known thrombocytopenia (platelet count < 100•109•L-1) -Known anaemia (haemoglobin < 100 g•L-1) -Need of anticoagulant treatment for disorders other than VTE -Recent unstable cardiovascular disease, such as uncontrolled hypertension at the time of enrolment (investigator's judgement), acute bacterial endocarditis or history of myocardial infarction within the last 3 months -Elevated AST or ALT > 2x ULN based on the local lab results obtained at screening and prior to randomisation (or central screening lab if available on time) -Liver disease expected to have any potential impact on survival (e.g. acute hepatitis, or possibly active hepatitis B, hepatitis C or cirrhosis, but not Gilbert's syndrome or hepatitis A with complete recovery) -Patients who have developed transaminase elevations upon exposure to ximelagatran -Severe renal impairment (estimated creatinine clearance <= 30 ml/min) -Women who are pregnant, nursing 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) -Participation in another clinical trial with an investigational drug during the last 30 days, except for the RE-COVER and RE-COVER 2 trials, or previous participation in this study -Patients considered unsuitable for inclusion by the investigator, e.g. because considered unreliable to comply with 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) -In case of anticipated study related diagnostic procedures requiring contrast medium (e.g. contrast venography or pulmonary angiography): -Elevated serum creatinine, which in the investigator's opinion contraindicates these examinations -Known allergy to radio opaque contrast media or iodine, which in the investigator's opinion contraindicates these examinations |
| -Trombosi venosa profonda o embolia polmonare sintomatica allo screening; -Embolia polmonare con insorgenza diversa dagli arti inferiori (per esempio arti superiori o cuore) -Presenza o previsione di inserzione di un filtro nella vena cava; -Interruzione della terapia anticoagulante per due o piu` settimane durante il periodo di trattamento di 3-6 mesi per il precedente evento tromboembolico venoso; -Pazienti che, secondo l'opinione dello sperimentatore, non possono essere trattati con warfarin; -Allergia a warfarin o a dabigatran o a uno degli eccipienti dei farmaci in studio; -Pazienti che, a giudizio dello sperimentatore, hanno un rischio eccessivo di sanguinamento per esempio a causa di: -Disordini emorragici o diatesi emorragica, -Traumi o interventi chirurgici maggiori nell'ultimo mese o per un periodo maggiore se permane un rischio eccessivo di sanguinamenti, o intervento chirurgico programmato; -Una qualsiasi delle seguenti patologie intracraniche: neoplasia, malformazione artero-venosa o aneurisma; -Storia di sanguinamenti intracranici, intraoculari, spinali, retroperitoneali o intrarticolari non traumatici; -Emorragia gastrointestinale negli ultimi 3 mesi; -Ulcera gastroduodenale sintomatica o documentata endoscopicamente negli ultimi 30 giorni; -Trattamento con trombolitici nei 14 giorni precedenti l'arruolamento; -Previsione di dover somministrare farmaci non permessi durante il periodo di trattamento; -Trombocitopenia nota (piastrine < 100x109/L); -Anemia nota (emoglobina < 100 g/l); -Necessita` di terapia anticoagulante per disordini diversi dal tromboembolismo venoso; -Recente malattia cardiovascolare instabile quale ipertensione arteriosa non controllata al momento dell'arruolamento (a giudizio dello sperimentatore), endocardite batterica acuta, o storia di infarto miocardico negli ultimi 3 mesi; -Elevati valori di AST o ALT > 2 volte il limite superiore di normalita` del laboratorio locale ottenuti allo screening e prima della randomizzazione (o laboratorio centralizzato se ottenuto in tempo) -Malattia epatica che potrebbe avere un potenziale impatto sulla sopravvivenza (per es. epatite acuta o epatite B possibilmente attiva, epatite C o cirrosi, ma non la sindrome di Gilbert o l'epatite A con guarigione completa); -Pazienti che hanno presentato aumento delle transaminasi con il trattamento con ximelagatran; -Insufficienza renale severa (clearance della creatinina < 30 ml/min); -Donne in gravidanza o donne in eta` fertile che rifiutano di utilizzare un metodo contraccettivo clinicamente valido per tutta la durata dello studio (NOTA: Prima dell'arruolamento nello studio, per le donne in eta` fertile, dovra` essere disponibile un test di gravidanza negativo) -Partecipazione a un altro studio clinico con un farmaco sperimentale negli ultimi 30 giorni, eccetto gli studi RE-COVER e RE-COVER 2, o precedente partecipazione a questo studio; -Pazienti considerati dallo sperimentatore inadatti all'inclusione, per es. perche` considerati inaffidabili a seguire le procedure di follow up dello studio e/o la somministrazione del farmaco, pazienti con aspettativa di vita inferiore alla durata dello studio a causa di malattie concomitanti, pazienti le cui condizioni, secondo l'opinione dello sperimentatore, non permettono una partecipazione allo studio sicura (per es. tossicodipendenza, alcolismo) -In caso di previsione di procedure diagnostiche correlate allo studio che richiedono la somministrazione di mezzo di contrasto (per es. venografia o angiografia polmonare): -Valore elevato di creatininemia che secondo l'opinione dello sperimentatore controindica questi esami -Allergia nota ai mezzi di contrasto radio opachi o iodati che secondo l'opinione dello sperimentatore controindica questi esami. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Composite of recurrent symptomatic venous thromboembolism (VTE) and deaths related to VTE during the treatment period. VTE is defined as the composite incidence of DVT and PE |
| composito di recidiva di tromboembolia venosa sistematica (TEV) e morte correlate alla TEV durante il periodo di trattamento. TEV definito come il composito di incidenze di TVP e EP |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 10 |
| 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 | 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
| |
| 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 | 40 |
| 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 | 43 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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