E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Intermediate-Risk Pulmonary Embolism |
Akutna pljučna embolija |
|
E.1.1.1 | Medical condition in easily understood language |
Acute Pulmonary Embolism |
Akutna embolija |
|
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 | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10037379 |
E.1.2 | Term | Pulmonary embolism and thrombosis |
E.1.2 | System Organ Class | 100000005124 |
|
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 determine whether treatment of acute intermediate-risk PE (as defined by the inclusion and exclusion criteria) with parenteral anticoagulation for at least 72 hours after diagnosis, followed by dabigatran over 6 months, is effective and safe. |
Primarni cilj je ugotoviti, ali je parenteralno zdravljenje akutne pljučne embolije z zmernim tveganjem (kot to opredeljujejo merila za vključitev in izključitev) z zdravilom proti strjevanju v obdobju najmanj 72 ur po diagnozi, ki mu sledi šestmesečno zdravljenje z zdravilom dabigatran, učinkovito in varno. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the recovery of right ventricular function over the first 6±1 days after the PE diagnosis, or upon discharge, and to evaluate its importance for the 6-month prognosis of patients with intermediate-risk PE. |
Sekundarni cilj je oceniti obnovitev delovanja desnega prekata v prvih 6 ± 1 dneh zdravljenja ali ob odpustu in oceniti pomen za šestmesečno prognozo pri bolnikih s PE z zmernim tveganjem |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Age ≥18 years; 2) Objectively confirmed diagnosis of acute PE by multidetector CT angiography, ventilation/perfusion lung scan, or selective invasive pulmonary angiography, according to established diagnostic criteria; 3) Absence of hemodynamic collapse/decompensation at presentation; 4) Intermediate-risk category of PE severity indicated by the presence of at least one of the following a, b, or c criteria:a) At least one sign of RV pressure overload/dysfunction on CT angiography or echocardiography: a1) on CT angiography, RV pressure overload/dysfunction is defined as RV/LV end-diastolic diameter ratio >1.0; or a2) on echocardiography, RV pressure overload/dysfunction is defined by the presence of at least one of the following findings: • RV/LV end-diastolic diameter ratio >1.0 (apical or subcostal 4-chamber view); • RV end-diastolic diameter >30 mm (parasternal long-axis or short-axis view); • RV free wall hypokinesis (any view); • Tricuspid regurgitant jet velocity >2.6 m/s from the apical or subcostal 4-chamber view, or the parasternal short-axis view; • Absence of inspiratory collapse of the inferior vena cava. b) Signs of myocardial injury as indicated by elevated troponin levels: • Troponin elevation is defined as an abnormal result of any validated troponin test based on the reference values determined by the local Department of Clinical Chemistry at each participating site; c) Signs of (RV) failure as indicated by NT-proBNP levels >600 pg/ml 5) Signed and dated informed consent of the subject available. |
Ključna merila za vključitev: 1) starost ≥ 18 let; 2) diagnoza akutne PE, v skladu z uveljavljenimi merili za diagnozo objektivno potrjena z angiografijo z večdetektorskim CT, ventilacijsko- perfuzijsko scintigrafijo pljuč ali selektivno invazivno angiografijo pljuč; 3) odsotnost hemodinamičnega kolapsa/dekompenzacije ob nastopu; 4) kategorija PE z zmernim tveganjem, na kar kaže prisotnost najmanj enega od meril a, b ali c: a) najmanj en znak čezmernega tlaka/disfunkcije DV pri angiografiji s pomočjo računalniške tomografije (CT) ali pri ehokardiografiji (8,23): a1) pri angiografiji s pomočjo CT sta čezmerni tlak/disfunkcija DV opredeljena kot razmerje premera DV/LV na koncu diastole > 1,0; ali a2) pri ehokardiografiji sta čezmerni tlak/disfunkcija DV opredeljena kot prisotnost najmanj ene od naslednjih ugotovitev: • razmerje premera DV/LV na koncu diastole > 1,0 (apikalni ali subkostalni pogled 4 votlin); • premer DV na koncu diastole > 30 mm (parasternalni pogled v dolgi ali kratki osi); • hipokinezija proste stene DV (kateri koli pogled); • hitrost trikuspidalne regurgitacije > 2,6 m/s v apikalnem ali subkostalnem pogledu 4 votlin ali v parasternalnem pogledu v kratki osi; • odsotnost kolapsa spodnje votle vene ob vdihu; b) znaki poškodbe miokarda, na katero kažejo zvišane ravni troponina: • zvišanje troponina je opredeljeno kot nenormalen izid katerega koli validiranega testa troponina na podlagi referenčnih vrednosti, ki jih določa lokalni oddelek za klinično kemijo na vsakem posameznem sodelujočem mestu izvajanja študije; c) znaki odpovedi (DV), na kar kažejo ravni NT-proBNP > 600 pg/ml; 5) predložena podpisana in datirana informirana privolitev preiskovanca. |
|
E.4 | Principal exclusion criteria |
1) Pregnancy or women of childbearing potential who do not practice a medically accepted highly effective contraception during the trial and one month beyond; 2) Use of a fibrinolytic agent, surgical thrombectomy, interventional (catheter-directed) thrombus aspiration or lysis, or use of a cava filter to treat the index episode of PE; 3) Need for long-term treatment with a low molecular weight heparin, a vitamin K antagonists, or a new oral anticoagulant (rivaroxaban, dabigatran, apixaban or edoxaban), for an indication other than the index PE episode; or for antiplatelet agents except a etylsalicylic acid at a dosage ≤100 mg/day; 4) Active bleeding or known significant bleeding risk; 5) Renal insufficiency with estimated creatinine clearance <30 ml/min/1.73m2; 6) Non-compliance or inability to adhere to treatment or to the follow-up visits; 7) Life expectancy less than 6 months. |
Ključna merila za izključitev: 1) nosečnost ali ženske v rodni dobi, ki v času trajanja raziskave in en mesec po njej ne uporabljajo nobene medicinsko odobrene visoko učinkovite kontracepcije; 2) uporaba fibrinolitičnega sredstva, kirurška trombektomija, intervencijska (katetrska) aspiracija trombusa ali liza, ali uporaba votlega filtra za zdravljenje prve epizode PE; 3) potreba po dolgotrajnem zdravljenju z nizkomolekularnim heparinom, antagonisti vitamina K ali novim peroralnim antikoagulantom (rivaroksaban, dabigatran, apiksaban ali edoksaban) za druge indikacije in ne VTE; ali po antiagregacijskih zdravilih, razen acetilsalicilne kisline, v odmerku ≤ 100 mg/dan; 4) aktivna krvavitev ali znano tveganje velike krvavitve; 5) ledvična odpoved z ocenjenim očistkom kreatinina < 30 ml/min/1,73 m2; 6) neskladnost ali nezmožnost upoštevanja sheme zdravljenja ali kontrolnih pregledov; 7) pričakovano trajanje življenja manj kot 6 mesecev |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is whether symptomatic VTE or PE-related death occurs within the first 6 months of anticoagulation therapy (yes/no). Symptomatic VTE and PE-related death are defined in chapter 2.2 of the Trial protocol. |
Primarni izid je ugotovitev, ali se simptomatska VTE ali smrt v povezavi s PE pojavi v prvih 6 mesecih zdravljenja z antikoagulanti (da/ne). Simptomatska VTE ali smrt v povezavi s PE sta opredeljeni v poglavju 2.2 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months after anticoagulation therapy |
6 mesecih zdravljenja z antikoagulanti |
|
E.5.2 | Secondary end point(s) |
1) Recovery of RV function at 6±1 days after PE diagnosis, or upon discharge (whichever comes first), and at 6-month follow-up, as assessed by echocardiography; 2) Course of NT-proBNP levels during follow-up (measurement at baseline, 6±1 days or at discharge, and 6-month follow-up); 3) Death from any cause, or hemodynamic collapse or decompensation, within the first 30 days; 4) PE-related death, or PE-related hemodynamic collapse or decompensation, within the first 30 days; 5) Overall duration of hospital stay (index event and repeated hospitalizations due to PE [index or recurrent event] or to a bleeding event) within 6 months; 6) Death from any cause within 6 months. |
1. Obnovitev delovanja DV po 6 ± 1 dneh po diagnozi PE ali ob odpustu (kar nastopi prej) in ob kontrolnem pregledu po šestih mesecih, kar se oceni z ehokardiografijo 2. Potek ravni NT-proBNP med kontrolnim pregledom (meritev ob začetku, po 6 ± 1 dneh ali ob odpustu ter ob kontrolnem pregledu po šestih mesecih) 3. Smrt, ki je posledica katerega koli vzroka, ali hemodinamski kolaps ali dekompenzacija v prvih 30 dneh 4. Smrt v povezavi s PE ali hemodinamski kolaps ali dekompenzacija v povezavi s PE v prvih 30 dneh 5. Skupno trajanje hospitalizacije (začetni dogodek in ponavljajoče se hospitalizacije zaradi PE [začetni dogodek ali ponovitev] ali zaradi krvavitve) v šestih mesecih 6. Smrt, ki je posledica katerega koli vzroka, v šestih mesecih |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
30 days, 6 months after PE diagnosis |
30 dneh, 6 mesecev po diagnozi pljučne embolije |
|
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 | 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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
prospektivna multicentrična mednarodna intervencijska raziskava v klinični fazi IV z enim krakom |
single-arm, prospective, interventional |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
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 |
Austria |
Belgium |
Germany |
Italy |
Netherlands |
Poland |
Romania |
Serbia |
Slovenia |
Spain |
|
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
|
Last patient last visit (LPLV) |
zadnjega obiska zadnjega bolnika |
|
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |