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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Pulmonary Embolism
• Intervention / Treatment: Drug: Alteplase 20 Mg Powder for Solution for Injection Vial; Device: Ultrasound assisted Thrombolysis

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

• Study Type: Interventional
• Enrollment (Estimated): 210
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Bispebjerg, Denmark, DK2400
    • Copenhagen University Hospital Bispebjerg Hospital
  • Copenhagen, Denmark, DK2100
    • Copenhagen University Hospital Rigshospitalet
  • Herlev, Denmark, DK2730
    • Copenhagen University Hospital, Herlev Gentofte Hospital
  • Capital Region
    • Gentofte, Capital Region, Denmark, 2900
      • Copenhagen University Hospital Gentofte

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Miller score comparing low dose thrombolysis and heparin alone groups	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)	at 48 to 96 hours post randomization
Reduction i Miller score comparing low dose thrombolysis by iv and by USATgroups	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)	at 48 to 96 hours post randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of bleeding complications	Bleeding complications (major and minor bleeding complication according the TIMI classification)	Until hospital discharge, on average 1 week
Change in oxygen supplement (FiO2)	FiO2 (in %)	at 48 to 96 hours post randomization
Incidence of Pulmonary Hypertension	Incidence of TR gradient > 40 mmHg at 3 months follow-up echocardiography	3 months follow-up
Length of stay of index admission	Duration of index admission, including hospital based rehabilitation	End of study, expected to be 5 years
Dyspnea index by visual analogue scale	Dyspnea index (Visual analog scale) after 48-96 h and after 3 months	End of study, expected to be 5 years
Mortality rate	Mortality in the three groups (log-rank), and hazard ratio in multivariable analysis using the UFH/LMWH as reference	End of study, expected to be 5 years
6 minute walk distance af follow-up	6 minute walk distance at 3 months follow-up visit	3 months follow-up
Health related Quality of Life (PEmb-QoL)	Health related Quality of Life at 3 months follow-up using PEmb-QoL (Pulmonary Embolism Quality of Life) ranging from 0 to 100, higher score indicating worse Quality of Life	3 months follow-up
Health related Quality of Life (EQ-5D-5L)	5Q-5D-5L (EuroQoL 5 dimension, 5 level questionnaire, ranging from -0.59 to 1, where 1 is the best possible health state)	3 months follow-up

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: University Hospital Bispebjerg and Frederiksberg; Hillerod Hospital, Denmark; Herlev and Gentofte Hospital; Copenhagen University Hospital, Hvidovre

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2019
• Primary Completion (Actual): June 5, 2024
• Study Completion (Estimated): November 30, 2024

Study Registration Dates

• First Submitted: September 9, 2019
• First Submitted That Met QC Criteria: September 11, 2019
• First Posted (Actual): September 12, 2019

Study Record Updates

• Last Update Posted (Actual): November 15, 2024
• Last Update Submitted That Met QC Criteria: November 14, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Pulmonary Embolism; Embolism; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Fibrinolytic Agents; Tissue Plasminogen Activator
• Other Study ID Numbers: STRATIFY-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Main trial database

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes