E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Pulmonary Embolism, intermediate high risk (visible impact on right ventricular structure and function, and biochemical markers og myocardial damage according to the European Society of Cardiology Guidelines) |
|
E.1.1.1 | Medical condition in easily understood language |
Acute clot in the pulmonary circulation. Clotburdon of a magnitude that impacts right ventricular function |
|
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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037377 |
E.1.2 | Term | Pulmonary embolism |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal 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 |
To compare the efficacy of low dose thrombolytics administered intravenously or via pulmonary artery catheter to usual care (including heparins) on segemental pulmonary perfusion using the MIller Score |
|
E.2.2 | Secondary objectives of the trial |
Secondary outcomes: 1) Reduction in Miller Score comparing low dose rtPA by intravenous route and via USAT. 21) Reduction in D-dimer from baseline to 48-96h post intervention. 32) Incidence of TR gradient > 40 mmHg at 3 months follow-up echocardiography. 34) Relative reduction in TnI/T from baseline to 48-96 h post intervention. 45) Bleeding complications (major and minor bleeding complication according the TIMI classification). 56) Mortality in the three groups (log-rank) and hazard ratio in multivariable analysis using the UFH/LMWH as reference. 67) NT-pro-BNP at 3 months follow-up, 78) 6 minute walk distance at 3 months follow-up 89) Quality of life at 3 months follow-up comparing the three groups (SF-36 and 5Q-DL) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Age ≥ 18 years 2) Informed consent for trial participation 3) Intermediate high-risk PE according to ESC criteria 4) Thrombus visible in main, lobar or segmental pulmonary arteries on CT angiography 5) 14 days of symptoms or less
|
|
E.4 | Principal exclusion criteria |
1) Altered mental state (GCS < 14) 2) No qualifying CT angiography performed (> 24 hour since CT angiography) 3) Females of child bearing potential, unless negative HCG test is present 4) Thrombolysis for PE within 14 days of randomization 5) Thrombus passing through patent Foramen Ovale (risk of paradoxical embolism) 6) Ongoing oral anticoagulation therapy (heparins, aspirin, antiplatelet therapy and NOAC allowed) 7) Comorbidity making 6 months survival unlikely 8) Absolute contraindications for thrombolysis a. Hemorrhagic stroke or stroke of unknown origin at any time b. Ischemic stroke in the preceding 6 months c. Central nervous system damage or neoplasms d. Recent major trauma/surgery/head injury in the preceding 3 weeks e. Gastrointestinal bleeding within the last month f. Known bleeding risk Relative contraindications do not preclude randomization. Relative contraindications include: Transient ischemic attack in the preceding 6 months, Oral anticoagulant therapy, Pregnancy, or within one week pPost partum, Non-compressible puncture site, Traumatic resuscitation, Refractory hypertension (systolic blood pressure >180 mm Hg), Advanced liver disease, Infective endocarditis, Active peptic ulcer
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
CO-PRIMARY ENDPOINT • Reduction in modified Miller score (score of thrombus involvement and segmental flow)(13, 14)(13;14) comparing thrombolysis groups (combining groups with and without USAT) to heparin/LMWH groupgroup, p<0.01 (n=140 vs. n=70). • Reduction in modified Miller score (score of thrombus involvement and segmental flow)(13, 14) comparing thrombolysis administered by USAT or IV, p<0.04 (n=70 vs n=70)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoints are evaluated within 96 hours from randomization |
|
E.5.2 | Secondary end point(s) |
• Reduction in modified Miller score (score of thrombus involvement and segmental flow)(13;14) comparing the group treated with thrombolysis without USAT to thrombolysis with USAT • Reduction in D-dimer from baseline to 48-96h post randomization • Incidence of TR gradient > 40 mmHg at 3 months follow-up echocardiography • Relative reduction in TnI/T from baseline to 48-96 h post intervention • Bleeding complications (major and minor bleeding complication according the TIMI classification) • Dyspnea index (Visual analog scale) after 48-96 h and after 3 months • Mortality in the three groups (log-rank), and hazard ratio in multivariable analysis using the UFH/LMWH as reference • Reduction in NT-pro-BNP at 48-96 hours and 3 months • 6MWD at 3 months comparing the three groups • Quality of life at 3 months follow-up comparing the three groups (SF-36 and 5Q-DL) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints are evaluated within 3 months from randomization |
|
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 | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Unfractionated Heparin IV or Low molecular weight hearin (usual care) |
|
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 | 11 |
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 | 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 |