Pulmonary EmbolismPhase 2BETULANCT03854266
Low Dose Catheter Directed Thrombolysis for Acute Pulmonary Embolism
A Phase 2 study testing Low dose alteplase, Unfractionated heparin and Infusion catheter in people with Pulmonary Embolism, run by University of Aarhus at 1 site in Denmark.
Trial summary
BETULA trial will compare the efficacy of low dose catheter directed thrombolysis (CDT) to unfractioned heparin (UFH) in patients with intermediary-high risk pulmonary embolism (PE). Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Pulmonary Embolism
- What is being tested?
- Low dose alteplase, Unfractionated heparin and Infusion catheter
- Type of treatment
- Injection or infusion, Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteDenmark
- Study dates
- 10 Mar 2020to 10 Mar 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age > 17 and < 81 years
- Debut of symptoms <14 days
- Acute symptomatic Intermediate-high risk pulmonary embolism (PE, according to 2014 European Society of Cardiology guidelines) confirmed by computed tomography angiography (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 CTA or trans-thoracic echocardiography (TTE)
Who cannot join
- Significant bleeding risk or other contraindications to catheter directed thrombolysis (CDT) or unfractionated heparin*
- Not possible to perform CDT within 48 hours after diagnosis
- Pregnancy
- Cardiac arrest requiring cardiopulmonary resuscitation
- Life expectancy < 120 days
- Altered mental status such that the patient is unable to provide informed consent
- Suspected or known chronic thromboembolic pulmonary hypertension
- Sustained hypertension (>180 mmHg systolic and/or >105 mmHg diastolic)
Trial locations and contacts
1 site in 1 country.
Jens Erik Nielsen-Kudsk, MD, dMSc contact
Denmark1 site, 1 recruiting
- Recruiting
Aarhus University Hospital, Dep. Cardiology
Aarhus N, 8200
Asger Andersen, MD, PhD, 26363226, asgerandersen@gmail.com
Jacob G Schultz, MD, PhD, jacobgschultz@gmail.com
About this study
Official title: Low Dose Catheter Directed Thrombolysis for Acute Intermediary-high Risk Pulmonary Embolism
BETULA trial will compare the efficacy of low dose catheter directed thrombolysis (CDT) to unfractioned heparin (UFH) in patients with intermediary-high risk pulmonary embolism (PE).
Patients (n=60) with acute intermediary-high risk PE will be randomized 1:1 to UFH (bolus 80 international units per kilo (IU/kg)) followed by 18 IU/kg/hour until activated partial thromboplastin time (APTT) is 2-2.5 of reference value) or CDT (4mg alteplase (r-tPA) per catheter, infusion over 2 hours) in an open label, outcome assessor blinded, randomized, controlled trial. Primary efficacy endpoint is improvement in right-/left ventricular ratio 24 hours after randomization. Secondary endpoints are 30 days mortality, recurrent PE, length of hospital stay and reduction in thrombus burden evaluated by pulmonary CT angio. Safety endpoints are minor and major bleedings.
Read the detailed description
- Aim To investigate if low dose catheter directed fibrinolysis for 2 hours is superior to unfractioned heparin with regards to unloading the right ventricle in acute intermediate-high risk pulmonary embolism
- Methods 2.1 Study design The study is an open label, randomized, single center trial. Patients (n=60) with acute intermediate-high risk acute pulmonary embolism diagnosed with computed tomography pulmonary angiography (CTA) will be treated with unfractionated heparin (UFH) at the time of diagnosis and randomized 1:1 within 48 h to low dose catheter directed thrombolysis or continuation of UFH. Primary endpoint is improvement in right-to-left ventricular ratio (RV/LV ratio) evaluated by CTA 24 hours (±2h) after randomization. Secondary endpoints are 30 day mortality, reduction in thrombus burden evaluated by CTA, length of hospital stay and recurrent PE. Safety will be monitored as minor and major bleeding. 2.2 Patients Patients are eligible for inclusion if they apply to all inclusion and none of the exclusion criteria and give their informed written consent 2.2.1 Recruitment and informed consent Patients admitted to a hospital in Region Midt with acute pulmonary embolism will be screened for eligibility for inclusion in the trial by a local investigator at the day of admission. The local investigator will then contact the PI that will ensure that the patient is eligible for inclusion. All patients referred for possible inclusion will be registered as screened. If eligible for inclusion, the local investigator will give the verbal and written study information to the patient. The local investigator will do the best possible to avoid interruptions and the staff will be informed accordingly to ensure fewest possible interruptions during the verbal information. The patient will be informed that it is possible to have an assessor during the verbal information. After verbal and written information the patient will be given a minimum of 1/2 hour and up to 8 hours for reflection before giving their consent. The patient will also be informed, that they can withdraw their consent at any time. 2.2.2 Benefits, risk and safety The patients included in this trial will be treated with the highest known standard of care for their acute PE. If randomized to conventional treatment (UFH), there is no obvious benefit for the individual patient with regards to treatment, but the extra diagnostics may aid the treating physician to optimize their standard treatment. For patients randomized to CDT there is a potential benefit of treatment due to faster removal of thrombus mass in the pulmonary arteries. The biggest advantage of this trial is for future patients with acute PE, as this trial will aid future decisions with regards to treatment with CDT or UFH. Safety is discussed in section 12. 2.2.3 Patient discontinuation and substitution Patients that are included in the study but discontinue (any cause) before their follow-up CTA 24 hours after treatment will be excluded from the final data analysis and substituted by a new study patient. Data from patients that discontinue (any cause) after their follow-up 24 hours CTA will be included in the final analysis. Data from patients that withdraw their consent for study participation will be excluded and substituted by a new study patient, if the trial is still ongoing at time of withdrawal. 2.3 Treatment and Randomization 2.3.1 Randomization After study inclusion, patients will be transferred to Department of Cardiology, Aarhus University Hospital. Then, patients will be randomized to continue UFH with or without CDT. Patient data will be registered in the online case report form (CRF) hosted in a RedCap database and the RedCap database tool for randomization will be used for randomization to treatment. The recorded variable are listed in appendix 1. 2.6 Statistics A previous similar study using ultrasound assisted CDT (10-20 mg rt-PA over 15 hours) versus UFH ULTIMA found an improvement in RV/LV ratio of -0.3 (SD, 0.2) vs. -0.03 (SD, 0.16) with UFH alone. And the OPTALYSE(6) study found an improvement in RV/LV ratio of -0.46 (no SD reported, only abstract published) using 4/8 mg rt-PA over 2 hours. Using the most conservative result from the previous trials with a RV/LV difference of 0.17 between groups, and SD from a current unpublished PE study from our institution of 0.3, power of 0.8 and a significance level of 0.05 the sample size is calculated to be 21 patients in each treatment group. Based on this power calculation we plan to include a total of 60 patients randomized 1:1 with an interim analysis after the inclusion of 42 patients. All data with dichotomous outcome will be analyzed using the fisher's exact test. Between group comparison of continuous data will be compared using the two-sided unpaired t-test or Wilcoxon rank sum test. Within group comparison of continues data will be performed using the two-sided paired t-test and ordinal data with the Wilcoxon signed-rank test. Ordinal data between groups will be analyzed using a chi-square test. Data will be analyzed as intention to treat.
- Time Schedule In Region Midt, 350 patients with PE is admitted to the hospital each year. Based on a previous study at our institution including patients with intermediary-high risk PE patients we plan to include 20 patients/year over a 3 year period.
- Feasibility The Dep. of Cardiology, Aarhus University Hospital have a long tradition of including patients in randomized trials. All necessary equipment and personnel for the study is available at the department. Associate Professor Asger Andersen, MD, PhD (AA) and Professor Jens Erik Nielsen-Kudsk, MD, DMSc (JENK) will be principal investigators.
- Ethics The study will adhere to Danish laws of ethics and management of personal data. The study will not begin before it have been approved by The regional data monitoring board, the Regional Ethics Committee and the Danish Medicines Agency. The study will adhere to the standards of good clinical practice and it will be monitored by the Unit of "Good Clinical Practice" at Aalborg and Aarhus University Hospitals. The study will pay the outmost respect to the included patients mental and physical health and their personal integrity.
- Safety The treatment is considered safe and previous studies suggest that this approach may be better than conventional therapy. All patients will be monitored continuously with ECG, blood pressure and clinical status in the catheterization laboratorium and after return to the ward with blood pressure, pulse, respiratory frequency and clinical status minimum every hour until two hours after termination of alteplase infusion. If any suspected or confirmed complication occurs the physician on call, attending the ward, will be contacted to initiate relevant diagnostic testing and/or treatment. The staff and physicians attending the ward are well trained in attending critically ill patient including patients with acute PE and patients that have been catheterized. The invasive procedure will be performed by a trained invasive cardiologist whose expertise is to catheterize the pulmonary circulation. Using the low dose short period regime suggested in this protocol there have not been reported any bleedings in clinical studies. The patients included in the trial will be exposed to an extra CTA which exposes the patient to 4-8 millisievert which approximates the background radiation a person receives over 3 years and increases the risk of a fatal cancer from 25% to 25.045%. Patients randomized to CDT will receive an additional 1-2 millisievert from the fluoroscopy. The patients included in this study have an estimated 30 day mortality of 15% and solid preliminary data suggest the treatment to be effective and safe. Therefore it is the investigators opinion that the benefits of doing this study outweighs the risks.
- Publication The results from this trial will be published whether negative, neutral or positive. First author will be AA and last author JENK. Members of the steering committee and responsible investigators from each trial site will be co-authors. Other contributing members of the trial will be offered co-authorship if their contribution adheres to the Vancouver protocol for co-authorship.
- Perspectives This study will be the first randomized trial to investigate if low dose catheter based thrombolysis is superior to unfractioned heparin with regards to unloading the right ventricle in patients with acute intermediate-high risk pulmonary embolism. If efficient, the findings from this study may motivate a larger clinical trial with hard clinical endpoints.
- Conditions
- Pulmonary Embolism
- Being tested
- Low dose alteplase, Unfractionated heparin, Infusion catheter
- Medical subject headings
- Pulmonary Embolism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low dose alteplaseDrug
Also called alteplase
Low dose alteplase is 4 milligram per pulmonary artery (maximum dose 8 milligram) infused in the pulmonary arteries over 2 hours
Unfractionated heparinDrug
Also called heparin
Unfractioned heparin is administered in a peripheral vein with an initial dose of 80 international units per kilo (IU/kg) bolus followed by 18 IU/kg as continuous infusion with dose adjustment every 6 hours and once daily when activated partial thromboplastin time (APPT) is 1.5-2.3 times control value.
Infusion catheterDevice
Also called Unifuse
A sidehole catheter (Unifuse, AngioDynamics, US) catheter will be advanced to the pulmonary arteries to facilitate the catheter directed thrombolysis
| Study group | Role | What they receive |
|---|---|---|
| Catheter directed thrombolysis | Experimental | Low dose alteplase (4/8 milligram) will be infused over 2 hours locally in the pulmonary arteries at the site of the thrombus through an infusion catheter with sideholes (Unifuse, AngioDynamics, US) Receives: Drug: Low dose alteplase; Device: Infusion catheter |
| Unfractionated heparin | Active comparator | Initial dose of unfractionated heparin is 80 international units per kilo (IU/kg) bolus followed by 18 IU/kg as continuous infusion with dose adjustment every 6 hours and once daily when activated partial thromboplastin time is 1.5-2.3 times control value. Receives: Drug: Unfractionated heparin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Right ventricle divided by left ventricular diameter (RV/LV ratio)
Measured on ECG gated contrast enhanced computed tomography
Measured: 24 hours after intervention
Secondary outcomes (5)
Reduction in thrombus burden
A modified miller index till be measured on ECG gated contrast enhanced computed tomography
Measured: 24 hours after intervention
Thirty day mortality
The number of patients that are decease within 30 days after the intervention will be assessed from the patient files.
Measured: 30 days after intervention
Length of hospital stay
The length of hospital stay in days will be evaluated from the patient files
Measured: 3 months after intervention
Recurrent pulmonary embolism
Number of patients with recurrent pulmonary embolism will be evaluated from the patient files
Measured: 3 months after intervention
Lung perfusion
Lung perfusion will be evaluated and quantified with dual energy computed tomography
Measured: 24 hours after intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2019
- Study start10 Mar 2020
- Primary completion10 Mar 2023 (estimated)
- Study completion10 Mar 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Pulmonary EmbolismStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Aarhus
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Asger Andersen, MD, PhD, Principal investigator, Aarhus University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03854266
- Sponsor's protocol ID
- 190580-0001
- Acronym
- BETULA
- Status last verified
- Apr 2021
- First submitted
- 5 Feb 2019
- Last updated
- 28 Apr 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
- Individual data sharing
- Undecided
Publications
Tapson VF, Sterling K, Jones N, Elder M, Tripathy U, Brower J, Maholic RL, Ross CB, Natarajan K, Fong P, Greenspon L, Tamaddon H, Piracha AR, Engelhardt T, Katopodis J, Marques V, Sharp ASP, Piazza G, Goldhaber SZ. A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial. JACC Cardiovasc Interv. 2018 Jul 23;11(14):1401-1410. doi: 10.1016/j.jcin.2018.04.008.
PubMed 30025734Sogaard KK, Schmidt M, Pedersen L, Horvath-Puho E, Sorensen HT. 30-year mortality after venous thromboembolism: a population-based cohort study. Circulation. 2014 Sep 2;130(10):829-36. doi: 10.1161/CIRCULATIONAHA.114.009107. Epub 2014 Jun 26.
PubMed 24970783Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69, 3069a-3069k. doi: 10.1093/eurheartj/ehu283. Epub 2014 Aug 29. No abstract available.
PubMed 25173341Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Grunwald H, Empen K, Baumgartner I. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/CIRCULATIONAHA.113.005544. Epub 2013 Nov 13.
PubMed 24226805Engelberger RP, Spirk D, Willenberg T, Alatri A, Do DD, Baumgartner I, Kucher N. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis. Circ Cardiovasc Interv. 2015 Jan;8(1):e002027. doi: 10.1161/CIRCINTERVENTIONS.114.002027.
PubMed 25593121
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Low Dose Catheter Directed Thrombolysis for Acute Intermediary-high Risk Pulmonary Embolism
- ClinicalTrials.gov ID
- NCT03854266
- Acronym / sponsor ID
- BETULA / 190580-0001
- Conditions
- Pulmonary Embolism
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- Study start
- 10 Mar 2020 (actual)
- Primary completion
- 10 Mar 2023 (estimated)
- Study completion
- 10 Mar 2024 (estimated)
- First posted
- 26 Feb 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
BETULA trial will compare the efficacy of low dose catheter directed thrombolysis (CDT) to unfractioned heparin (UFH) in patients with intermediary-high risk pulmonary embolism (PE).
Patients (n=60) with acute intermediary-high risk PE will be randomized 1:1 to UFH (bolus 80 international units per kilo (IU/kg)) followed by 18 IU/kg/hour until activated partial thromboplastin time (APTT) is 2-2.5 of reference value) or CDT (4mg alteplase (r-tPA) per catheter, infusion over 2 hours) in an open label, outcome assessor blinded, randomized, controlled trial. Primary efficacy endpoint is improvement in right-/left ventricular ratio 24 hours after randomization. Secondary endpoints are 30 days mortality, recurrent PE, length of hospital stay and reduction in thrombus burden evaluated by pulmonary CT angio. Safety endpoints are minor and major bleedings.
Detailed description
- Aim To investigate if low dose catheter directed fibrinolysis for 2 hours is superior to unfractioned heparin with regards to unloading the right ventricle in acute intermediate-high risk pulmonary embolism
- Methods 2.1 Study design The study is an open label, randomized, single center trial. Patients (n=60) with acute intermediate-high risk acute pulmonary embolism diagnosed with computed tomography pulmonary angiography (CTA) will be treated with unfractionated heparin (UFH) at the time of diagnosis and randomized 1:1 within 48 h to low dose catheter directed thrombolysis or continuation of UFH. Primary endpoint is improvement in right-to-left ventricular ratio (RV/LV ratio) evaluated by CTA 24 hours (±2h) after randomization. Secondary endpoints are 30 day mortality, reduction in thrombus burden evaluated by CTA, length of hospital stay and recurrent PE. Safety will be monitored as minor and major bleeding. 2.2 Patients Patients are eligible for inclusion if they apply to all inclusion and none of the exclusion criteria and give their informed written consent 2.2.1 Recruitment and informed consent Patients admitted to a hospital in Region Midt with acute pulmonary embolism will be screened for eligibility for inclusion in the trial by a local investigator at the day of admission. The local investigator will then contact the PI that will ensure that the patient is eligible for inclusion. All patients referred for possible inclusion will be registered as screened. If eligible for inclusion, the local investigator will give the verbal and written study information to the patient. The local investigator will do the best possible to avoid interruptions and the staff will be informed accordingly to ensure fewest possible interruptions during the verbal information. The patient will be informed that it is possible to have an assessor during the verbal information. After verbal and written information the patient will be given a minimum of 1/2 hour and up to 8 hours for reflection before giving their consent. The patient will also be informed, that they can withdraw their consent at any time. 2.2.2 Benefits, risk and safety The patients included in this trial will be treated with the highest known standard of care for their acute PE. If randomized to conventional treatment (UFH), there is no obvious benefit for the individual patient with regards to treatment, but the extra diagnostics may aid the treating physician to optimize their standard treatment. For patients randomized to CDT there is a potential benefit of treatment due to faster removal of thrombus mass in the pulmonary arteries. The biggest advantage of this trial is for future patients with acute PE, as this trial will aid future decisions with regards to treatment with CDT or UFH. Safety is discussed in section 12. 2.2.3 Patient discontinuation and substitution Patients that are included in the study but discontinue (any cause) before their follow-up CTA 24 hours after treatment will be excluded from the final data analysis and substituted by a new study patient. Data from patients that discontinue (any cause) after their follow-up 24 hours CTA will be included in the final analysis. Data from patients that withdraw their consent for study participation will be excluded and substituted by a new study patient, if the trial is still ongoing at time of withdrawal. 2.3 Treatment and Randomization 2.3.1 Randomization After study inclusion, patients will be transferred to Department of Cardiology, Aarhus University Hospital. Then, patients will be randomized to continue UFH with or without CDT. Patient data will be registered in the online case report form (CRF) hosted in a RedCap database and the RedCap database tool for randomization will be used for randomization to treatment. The recorded variable are listed in appendix 1. 2.6 Statistics A previous similar study using ultrasound assisted CDT (10-20 mg rt-PA over 15 hours) versus UFH ULTIMA found an improvement in RV/LV ratio of -0.3 (SD, 0.2) vs. -0.03 (SD, 0.16) with UFH alone. And the OPTALYSE(6) study found an improvement in RV/LV ratio of -0.46 (no SD reported, only abstract published) using 4/8 mg rt-PA over 2 hours. Using the most conservative result from the previous trials with a RV/LV difference of 0.17 between groups, and SD from a current unpublished PE study from our institution of 0.3, power of 0.8 and a significance level of 0.05 the sample size is calculated to be 21 patients in each treatment group. Based on this power calculation we plan to include a total of 60 patients randomized 1:1 with an interim analysis after the inclusion of 42 patients. All data with dichotomous outcome will be analyzed using the fisher's exact test. Between group comparison of continuous data will be compared using the two-sided unpaired t-test or Wilcoxon rank sum test. Within group comparison of continues data will be performed using the two-sided paired t-test and ordinal data with the Wilcoxon signed-rank test. Ordinal data between groups will be analyzed using a chi-square test. Data will be analyzed as intention to treat.
- Time Schedule In Region Midt, 350 patients with PE is admitted to the hospital each year. Based on a previous study at our institution including patients with intermediary-high risk PE patients we plan to include 20 patients/year over a 3 year period.
- Feasibility The Dep. of Cardiology, Aarhus University Hospital have a long tradition of including patients in randomized trials. All necessary equipment and personnel for the study is available at the department. Associate Professor Asger Andersen, MD, PhD (AA) and Professor Jens Erik Nielsen-Kudsk, MD, DMSc (JENK) will be principal investigators.
- Ethics The study will adhere to Danish laws of ethics and management of personal data. The study will not begin before it have been approved by The regional data monitoring board, the Regional Ethics Committee and the Danish Medicines Agency. The study will adhere to the standards of good clinical practice and it will be monitored by the Unit of "Good Clinical Practice" at Aalborg and Aarhus University Hospitals. The study will pay the outmost respect to the included patients mental and physical health and their personal integrity.
- Safety The treatment is considered safe and previous studies suggest that this approach may be better than conventional therapy. All patients will be monitored continuously with ECG, blood pressure and clinical status in the catheterization laboratorium and after return to the ward with blood pressure, pulse, respiratory frequency and clinical status minimum every hour until two hours after termination of alteplase infusion. If any suspected or confirmed complication occurs the physician on call, attending the ward, will be contacted to initiate relevant diagnostic testing and/or treatment. The staff and physicians attending the ward are well trained in attending critically ill patient including patients with acute PE and patients that have been catheterized. The invasive procedure will be performed by a trained invasive cardiologist whose expertise is to catheterize the pulmonary circulation. Using the low dose short period regime suggested in this protocol there have not been reported any bleedings in clinical studies. The patients included in the trial will be exposed to an extra CTA which exposes the patient to 4-8 millisievert which approximates the background radiation a person receives over 3 years and increases the risk of a fatal cancer from 25% to 25.045%. Patients randomized to CDT will receive an additional 1-2 millisievert from the fluoroscopy. The patients included in this study have an estimated 30 day mortality of 15% and solid preliminary data suggest the treatment to be effective and safe. Therefore it is the investigators opinion that the benefits of doing this study outweighs the risks.
- Publication The results from this trial will be published whether negative, neutral or positive. First author will be AA and last author JENK. Members of the steering committee and responsible investigators from each trial site will be co-authors. Other contributing members of the trial will be offered co-authorship if their contribution adheres to the Vancouver protocol for co-authorship.
- Perspectives This study will be the first randomized trial to investigate if low dose catheter based thrombolysis is superior to unfractioned heparin with regards to unloading the right ventricle in patients with acute intermediate-high risk pulmonary embolism. If efficient, the findings from this study may motivate a larger clinical trial with hard clinical endpoints.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Catheter directed thrombolysis | Experimental | Drug: Low dose alteplase, Device: Infusion catheterLow dose alteplase (4/8 milligram) will be infused over 2 hours locally in the pulmonary arteries at the site of the thrombus through an infusion catheter with sideholes (Unifuse, AngioDynamics, US) |
| Unfractionated heparin | Active comparator | Drug: Unfractionated heparinInitial dose of unfractionated heparin is 80 international units per kilo (IU/kg) bolus followed by 18 IU/kg as continuous infusion with dose adjustment every 6 hours and once daily when activated partial thromboplastin time is 1.5-2.3 times control value. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age > 17 and < 81 years
- Debut of symptoms <14 days
- Acute symptomatic Intermediate-high risk pulmonary embolism (PE, according to 2014 European Society of Cardiology guidelines) confirmed by computed tomography angiography (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 CTA or trans-thoracic echocardiography (TTE)
Key exclusion criteria (8 listed)
- Significant bleeding risk or other contraindications to catheter directed thrombolysis (CDT) or unfractionated heparin*
- Not possible to perform CDT within 48 hours after diagnosis
- Pregnancy
- Cardiac arrest requiring cardiopulmonary resuscitation
- Life expectancy < 120 days
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Low dose alteplaseAlso: alteplaseLow dose alteplase is 4 milligram per pulmonary artery (maximum dose 8 milligram) infused in the pulmonary arteries over 2 hours | Drug | Catheter directed thrombolysis |
| Unfractionated heparinAlso: heparinUnfractioned heparin is administered in a peripheral vein with an initial dose of 80 international units per kilo (IU/kg) bolus followed by 18 IU/kg as continuous infusion with dose adjustment every 6 hours and once daily when activated partial thromboplastin time (APPT) is 1.5-2.3 times control value. | Drug | Unfractionated heparin |
| Infusion catheterAlso: UnifuseA sidehole catheter (Unifuse, AngioDynamics, US) catheter will be advanced to the pulmonary arteries to facilitate the catheter directed thrombolysis | Device | Catheter directed thrombolysis |
Primary outcome
Right ventricle divided by left ventricular diameter (RV/LV ratio)
Time frame: 24 hours after intervention
Measured on ECG gated contrast enhanced computed tomography
5 secondary outcomes
Reduction in thrombus burden
Time frame: 24 hours after intervention
Thirty day mortality
Time frame: 30 days after intervention
Length of hospital stay
Time frame: 3 months after intervention
Recurrent pulmonary embolism
Time frame: 3 months after intervention
Lung perfusion
Time frame: 24 hours after intervention
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2021.
- Background: PubMed 30025734Tapson VF, Sterling K, Jones N, Elder M, Tripathy U, Brower J, Maholic RL, Ross CB, Natarajan K, Fong P, Greenspon L, Tamaddon H, Piracha AR, Engelhardt T, Katopodis J, Marques V, Sharp ASP, Piazza G, Goldhaber SZ. A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial. JACC Cardiovasc Interv. 2018 Jul 23;11(14):1401-1410. doi: 10.1016/j.jcin.2018.04.008.
- Background: PubMed 24970783Sogaard KK, Schmidt M, Pedersen L, Horvath-Puho E, Sorensen HT. 30-year mortality after venous thromboembolism: a population-based cohort study. Circulation. 2014 Sep 2;130(10):829-36. doi: 10.1161/CIRCULATIONAHA.114.009107. Epub 2014 Jun 26.
- Background: PubMed 25173341Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69, 3069a-3069k. doi: 10.1093/eurheartj/ehu283. Epub 2014 Aug 29. No abstract available.
- Background: PubMed 24226805Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Grunwald H, Empen K, Baumgartner I. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/CIRCULATIONAHA.113.005544. Epub 2013 Nov 13.
- Background: PubMed 25593121Engelberger RP, Spirk D, Willenberg T, Alatri A, Do DD, Baumgartner I, Kucher N. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis. Circ Cardiovasc Interv. 2015 Jan;8(1):e002027. doi: 10.1161/CIRCINTERVENTIONS.114.002027.
- Individual participant dataSharing planned: Undecided
Related trials for Pulmonary Embolism
RecruitingObservational study
Study of the Long-Term Safety and Outcomes of Treating Pulmonary Embolism With the Indigo Aspiration System
Pulmonary Embolism
Not yet recruiting
Pilot Study Evaluating Catheter Directed Thrombolysis Device in Acute Intermediate Risk Pulmonary Embolism
Pulmonary Embolism (PE), Pulmonary Embolism With Right Ventricle Enlargement
RecruitingObservational study
Inari VISION Registry
Pulmonary Embolism
RecruitingPhase 3
Treatment and Secondary Prevention of Venous Thromboembolism (VTE) in Adult Participants With Solid and Hematologic Cancers
Venous Thromboembolism (VTE)
RecruitingPhase 3
REGN7508 in Adult Participants for Prevention of Cancer-Associated Thrombosis
Cancer-Associated Thrombosis (CAT)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jens Erik Nielsen-Kudsk, MD, dMSc contact
Asger Andersen, MD, PhD principal investigator
Aarhus University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Low dose alteplase, Unfractionated heparin and Infusion catheter in people with Pulmonary Embolism, run by University of Aarhus at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 28 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Asger Andersen, MD, PhD (+45-26363226, asger.andersen@clin.au.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Right ventricle divided by left ventricular diameter (RV/LV ratio) (time frame: 24 hours after intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03854266, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2021.