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Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism (STRATIFY)

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ClinicalTrials.gov Identifier: NCT04088292
Recruitment Status : Recruiting
First Posted : September 12, 2019
Last Update Posted : September 12, 2019
Sponsor:
Collaborators:
Herlev and Gentofte Hospital
University Hospital Bispebjerg and Frederiksberg
Hillerod Hospital, Denmark
Copenhagen University Hospital, Hvidovre
Information provided by (Responsible Party):
Jesper Kjaergaard, Rigshospitalet, Denmark

Brief Summary:
Open label clinical randomized trial comparing three strategies for managing acute intermediate-high risk pulmonary embolism

Condition or disease Intervention/treatment Phase
Pulmonary Embolism Drug: Alteplase 20 Mg Powder for Solution for Injection Vial Device: Ultrasound assisted Thrombolysis Phase 3

Detailed Description:

Trial acronym: STRATIFY Background: Intermediate-high risk pulmonary embolism (PE) is associated with a significant risk of death or hemodynamic deterioration. The optimal treatment strategy should balance efficacy in reducing thrombus burden and hemodynamic compromise with risk of complications, in particular bleeding. Previous studies have investigated conventional high-dose, short term thrombolysis by (rtPA), finding a reduction in risk hemodynamic deterioration, but no reduction in mortality and a substantial increase in significant bleeding complications.

Catheter based techniques and low dose thrombolysis may offer lower risk of complication with reasonable efficacy. Such studies have not been performed in RCTs with a reasonable sample size, and no study have compared low dose intravenous thrombolysis and catheter based techniques.

The current trial addresses this paucity of data by randomizing patients to one of three treatment modalities:

Intervention: 1:1:1 randomization, stratified for site to

  • UltraSound Assisted Thrombolysis (USAT) with low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus unfractionated heparin (UFH) or low molecular weight heparin (LMWH) within 12 hours of randomization
  • Intravenous low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus UFH or low molecular weight heparin (LMWH).
  • UFH or low molecular weight heparin (LMWH) only (with option for conventional thrombolysis according to local protocols for hemodynamic deterioration) Design: Regional collaborative, randomized trial with 1:1:1 allocation of 210 patients with acute intermediate-high risk PE with no absolute contraindications to thrombolysis

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized clinical trial with 1:1:1 allocation to treatment strata
Masking: Single (Outcomes Assessor)
Masking Description: Primary endpoint will be assessed by assessor blinded to the intervention
Primary Purpose: Treatment
Official Title: Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism
Actual Study Start Date : June 6, 2019
Estimated Primary Completion Date : June 5, 2021
Estimated Study Completion Date : October 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: USAT + low dose thrombolysis
UltraSound Assisted Thrombolysis (USAT) with low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus unfractionated heparin (UFH) or low molecular weight heparin (LMWH) within 12 hours of randomization
Drug: Alteplase 20 Mg Powder for Solution for Injection Vial
Low dose alteplase delivered IV or bu Ultrasound Assisted Thrombolysis device

Device: Ultrasound assisted Thrombolysis
Ultrasound assisted thrombolysis (USAT)

Active Comparator: Low dose thrombolysis
Intravenous low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus UFH or low molecular weight heparin (LMWH).
Drug: Alteplase 20 Mg Powder for Solution for Injection Vial
Low dose alteplase delivered IV or bu Ultrasound Assisted Thrombolysis device

No Intervention: Heparin alone
UFH or low molecular weight heparin (LMWH) only (with option for conventional thrombolysis according to local protocols for hemodynamic deterioration)



Primary Outcome Measures :
  1. Reduction in Miller score comparing low dose thrombolysis and heparin alone groups [ Time Frame: at 48 to 96 hours post randomization ]
    Reduction in Miller Score and on follow-up (48-96 h) CT pulmonary Angiography comparing low-dose rtPA (±USAT) to UFH/LMWH group (p<0.01, N=210)

  2. Reduction i Miller score comparing low dose thrombolysis by iv and by USATgroups [ Time Frame: at 48 to 96 hours post randomization ]
    reduction in Miller Score and on follow-up (48-96 h) CT pulmonary Angiography comparing low-dose rtPA by USAT to iv, p<0.04, N=140)


Secondary Outcome Measures :
  1. Incidence of bleeding complications [ Time Frame: Until hospital discharge, on average 1 week ]
    Bleeding complications (major and minor bleeding complication according the TIMI classification)

  2. Length of stay of index admission [ Time Frame: End of study, expected to be 2 years ]
    Duration of index admission, including hospital based rehabilitation

  3. Dyspnea index by visual analogue scale [ Time Frame: End of study, expected to be 2 years ]
    Dyspnea index (Visual analog scale) after 48-96 h and after 3 months

  4. Change in oxygen supplement (FiO2) [ Time Frame: at 48 to 96 hours post randomization ]
    FiO2 (in %)

  5. Mortality rate [ Time Frame: End of study, expected to be 2 years ]
    Mortality in the three groups (log-rank), and hazard ratio in multivariable analysis using the UFH/LMWH as reference

  6. Reduction in D-dimer values [ Time Frame: at 48 to 96 hours post randomization ]
    Reduction in D-dimer from baseline to 48-96h post randomization

  7. Incidence of Pulmonary Hypertension [ Time Frame: 3 months follow-up ]
    Incidence of TR gradient > 40 mmHg at 3 months follow-up echocardiography

  8. Reduction in troponin levels [ Time Frame: at 48 to 96 hours post randomization ]
    Relative reduction in TnI/T from baseline to 48-96 h post intervention

  9. Reduction in NT-pro-BNP levels [ Time Frame: 3 months follow-up ]
    Reduction in NT-pro-BNP at 48-96 hours and 3 months



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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

    1. Hemorrhagic stroke or stroke of unknown origin at any time
    2. Ischemic stroke in the preceding 6 months
    3. Central nervous system damage or neoplasms
    4. Recent major trauma/surgery/head injury in the preceding 3 weeks
    5. Gastrointestinal bleeding within the last month
    6. Known bleeding risk

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04088292


Contacts
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Contact: Jesper Kjærgaard, MD PhD DMSc +45 35450969 jesper.kjaergaard.05@regionh.dk
Contact: Lia Bang, MD PhD +45 35453545 lia.evi.bang@regionh.dk

Locations
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Denmark
Copenhagen University Hospital Bispebjerg Hospital Not yet recruiting
Bispebjerg, Denmark, DK2400
Contact: Michael Egstrup, MD PhD    +45 38 63 50 00      
Copenhagen University Hospital Rigshospitalet Recruiting
Copenhagen, Denmark, DK2100
Contact: Lia E Bang, MD PhD    +45 3545 3545    lia.evi.bang@regionh.dk   
Copenhagen University Hospital, Herlev Gentofte Hospital Not yet recruiting
Herlev, Denmark, DK2730
Contact: Søren Fanø, MD PhD    +45 38 68 38 68      
Sponsors and Collaborators
Rigshospitalet, Denmark
Herlev and Gentofte Hospital
University Hospital Bispebjerg and Frederiksberg
Hillerod Hospital, Denmark
Copenhagen University Hospital, Hvidovre

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Responsible Party: Jesper Kjaergaard, Sponsor, Primary investigator, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT04088292     History of Changes
Other Study ID Numbers: STRATIFY-1
First Posted: September 12, 2019    Key Record Dates
Last Update Posted: September 12, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Main trial database

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Pulmonary Embolism
Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Heparin
Calcium heparin
Tissue Plasminogen Activator
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action