E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute intermediary-high risk pulmonary embolism
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E.1.1.1 | Medical condition in easily understood language |
Acute pulmonary embolism is a condition where blood clots occlude the pulmonary circulation. This causes strain of the right heart, as it is forced to work harder to pump blood through the lungs. |
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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 | 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 |
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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 |
To investigate if low dose catheter directed fibrinolysis for 2 h is superior to unfractioned heparin with regards to unloading the right ventricle in acute intermediate-high risk pulmonary embolism.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age > 17 and < 81 years - Debut of symptoms <14 days - Acute symptomatic Intermediate-high risk PE (according to 2014 ESC guidelines) confirmed by CTA with the embolus located in at least one proximal lower lobe or main pulmonary artery. - Right-to-left ventricular dimension ratio >1.0 on contrast enhanced computed tomography or transthoracic echocardiography.
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E.4 | Principal exclusion criteria |
- Significant bleeding risk or other contraindications to catheter directed trombolysis or unfractioned heparin.* - Not possible to perform catheter directed trombolysis within 48 h after diagnosis - Known pregnancy or positive urine hCG screening test in fertile women** - Cardiac arrest requiring cardiopulmonary resuscitation - Life expectancy < 120 days - Altered mental status such that the patient is unable to provide informed consent - Chronic thromboembolic pulmonary hypertension - Sustained hypertension (>180 mmHg systolic and/or >105 mmHg diastolic)
*Treated with thrombolytics for the index ** Fertile women will be screened for pregnancy with a blood hCG screening test before inclusion if they are not on any contraceptives. |
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E.5 End points |
E.5.1 | Primary end point(s) |
improvement in right-to-left ventricular ratio (RV/LV-ratio) measured on an ecg gated CTA in the transverse four chamber view 1 cm above the atrio-ventricular plane as used by others in similar studies. All analysis will be performed by a core facility with a trained investigator, not affiliated to the study protocol and blinded to the treatment.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
A CTA will be performed after inclusion, but before randomization and this will be repeated 24h after randomization. |
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E.5.2 | Secondary end point(s) |
Efficacy Endpoints: Reduction in thrombus burden The pre and post CTAs will be analyzed using the modified Miller score to estimate the change in clot burden between treatment groups. The analysis will be performed by a core facility with a trained investigator, not affiliated to the study protocol and blinded to the treatment.
Lung perfusion The CT scan will be recorded using a dual energy CT technique which will allow for quantification of lung perfusion. The analysis will be performed by a core facility with a trained investigator, not affiliated to the study protocol and blinded to the treatment.
Thirty day mortality Thirty day mortality will be obtained from the electronic patient files.
Length of hospital stay The length of hospital stay is at the discretion of the treating physician and will be registered in the CRF based on the electronic patient file.
Recurrent PE Information regarding recurrent PE will be obtained from the patient file from the routine follow-up clinical visit 90 days after discharge.
Minor and major bleeding Minor bleeding will be classified as clinical overt bleeding that does not fulfill the criteria of a major bleeding. Major bleeding is defined as overt bleeding that involves a critical site (intramuscular with compartment syndrome, intracranial, intraspinal, retropretoneal, intraocular, intraarticular or pericardial), or is associated with a fall in hemoglobin of >2g/dl or the need of transfusion with 2 or more units of red blood cells. Bleeding events will be recorded during the hospital stay during the daily rounds.
Exhaled breath condensate Protein analysis for biomarkers of right heart strain, inflammation and coagulation will be analyzed in exhaled breath condensate (EBC). EBC will be collected by use of the commercially available RTube system after inclusion and repeated after treatment and analyzed by label free quantitative nano liquid chromatography - tandem mass spectrometry.
Serious Adverse Event/reaction includes but may not be limited to events that are: Fatal, life threatening, hospitalization or prolonging existing hospitalization, significant or persistant disability, congenital abnormality. The serious adverse event/reaction suggest a hazard or side effect defined by regulatory agencies and not by the investigator or sponsors opinion. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Reduction in thrombus burden and Lung perfusion are both obtained from CT scans performed before randomization and repeated 24h after randomization.
Thirty day mortality is evaluated 30 days from randomization.
Information regarding recurrent PE will obtained 90 days post discharge.
Minor and major bleeding events will be recorded during the hospital stay during the daily rounds.
Exhaled breath condensate will be collected after inclusion but before randomization and again 24h after randomization.
Serious adverse events/reactions will be registered from the time of inclusion until the follow up visit at 3 months. |
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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) | 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 |
Unfractioned heparin alone (standard therapy) |
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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
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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 | 6 |
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 | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |