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Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism (OPTALYSE PE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02396758
Recruitment Status : Active, not recruiting
First Posted : March 24, 2015
Last Update Posted : September 30, 2019
Sponsor:
Information provided by (Responsible Party):
EKOS Corporation

Brief Summary:
The objective is to determine the optimum dose of thrombolytic and duration of the ultrasound procedure (together defined as the APT Procedure) as a treatment for acute submassive pulmonary embolism (PE). Symptomatic submassive PE are participants with acute (less than or equal to [≤]14 days) PE with normal systemic arterial blood pressure (greater than [>] 90 mmHg) and evidence of RV dysfunction (right ventricular to left ventricular diameter ratio, that is; RV/LV ratio greater than or equal to [≥] 0.9). Participants with submassive PE will be randomized to one of four APT treatment groups: ultrasound of 2 and 6 hours (hrs) with r-tPA 2 milligrams (mg)/hr/catheter and ultrasound 4 and 6 hours with r-tPA, 1 mg/hr/catheter. On 08 June 2016, randomization into treatment group 4 (APT/6 hours-r-tPA/2 mg/hr/catheter) was closed following a reported intracranial hemorrhage (ICH) and death in a study participant in this arm.

Condition or disease Intervention/treatment Phase
Pulmonary Embolism and Thrombosis Device: Ekosonic® Endovascular Device ultrasonic infusion catheter Biological: Recombinant tissue plasminogen activator Phase 4

Detailed Description:
This study is designed to investigate the lowest recombinant tissue plasminogen activator (r-tPA) dose-ultrasound treatment time required to achieve the same reductions in thrombus burden and associated improvement in physiologic parameters demonstrated in ULTIMA (EKOS 08 [NCT01166997]) and SEATTLE II (EKOS 09 [NCT01513759]). Results of this study are intended to inform the study design for further studies of the Acoustic Pulse Thrombolysis (APT) Procedure. Analysis of the first 100 evaluable participants in the United States study suggested a degree of equipoise between treatment groups 1, 2 and 3 of the protocol and therefore the sample size has been extended and additional sites in the United Kingdom (UK) National Health Service included, with a view to adding to the findings of the OPTALYSE study from sites in the UK and increasing the number of participants treated by treatment protocol.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 129 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of the OPTtimum Duration of Acoustic Pulse ThromboLYSis ProcEdure in the Treatment of Acute Submassive Pulmonary Embolism
Actual Study Start Date : June 12, 2015
Actual Primary Completion Date : April 30, 2019
Estimated Study Completion Date : January 15, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Alteplase

Arm Intervention/treatment
Experimental: APT/2 Hours-r-tPA/2 mg/hr/Catheter
A total of 4 or 8 mg r-tPA (as 2 mg/hour [hr]/catheter) will be delivered through Ekosonic® Endovascular Device (EKOS) ultrasonic infusion catheter for 2 hrs.
Device: Ekosonic® Endovascular Device ultrasonic infusion catheter
r-tPA will be administered via EKOS.
Other Names:
  • Acoustic Pulse Thrombolysis Procedure (APT Procedure)
  • EKOS

Biological: Recombinant tissue plasminogen activator
Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Other Name: r-tPA

Experimental: APT/4 Hours-r-tPA/1 mg/hr/Catheter
A total of 4 or 8 mg r-tPA (as 1 mg/hr/catheter) will be delivered through EKOS ultrasonic infusion catheter for 4 hrs.
Device: Ekosonic® Endovascular Device ultrasonic infusion catheter
r-tPA will be administered via EKOS.
Other Names:
  • Acoustic Pulse Thrombolysis Procedure (APT Procedure)
  • EKOS

Biological: Recombinant tissue plasminogen activator
Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Other Name: r-tPA

Experimental: APT/6 Hours-r-tPA/1 mg/hr/Catheter
A total of 6 or 12 mg r-tPA (as 1 mg/hr/catheter) will be delivered through EKOS ultrasonic infusion catheter for 6 hrs.
Device: Ekosonic® Endovascular Device ultrasonic infusion catheter
r-tPA will be administered via EKOS.
Other Names:
  • Acoustic Pulse Thrombolysis Procedure (APT Procedure)
  • EKOS

Biological: Recombinant tissue plasminogen activator
Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Other Name: r-tPA

Experimental: APT/6 Hours-r-tPA/2 mg/hr/Catheter
A total of 12 or 24 mg r-tPA (as 2 mg/hr/catheter) will be delivered through EKOS ultrasonic infusion catheter for 6 hrs.
Device: Ekosonic® Endovascular Device ultrasonic infusion catheter
r-tPA will be administered via EKOS.
Other Names:
  • Acoustic Pulse Thrombolysis Procedure (APT Procedure)
  • EKOS

Biological: Recombinant tissue plasminogen activator
Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Other Name: r-tPA




Primary Outcome Measures :
  1. Change From Baseline in the Right Ventricle (RV) Diameter-to-Left Ventricle (LV) Diameter Ratio to 48 ± 6 Hours After the Start of the APT Procedure [ Time Frame: Baseline, 48 hrs ± 6 hours ]
    Change from baseline in RV/LV will be determined by computed tomographic angiography (CTA).

  2. Number of Participants With Major Bleeding Within 72 Hours After Initiating the APT Procedure [ Time Frame: Day 3 (within 72 hours after initiating the APT procedure) ]
    Criteria for major bleeding events, as defined by the International Society on Thrombosis and Haemostasis (ISTH): 1. Fatal bleeding and/or; 2. Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome) and/or; 3. Bleeding causing a fall in hemoglobin level of 20 grams/liter (g/L) or more, or leading to transfusion of two or more units of whole blood or red blood cells.


Secondary Outcome Measures :
  1. Percentage of Participants With Treatment Success of an APT Procedure [ Time Frame: From Baseline up to Day 30 ]
    Treatment success of an APT procedure will be assessed by an Adjudication Committee that is blinded to the participant's treatment. The criteria for treatment success are defined as follows: A decrease in RV/LV from baseline to 48 hours after the start of the procedure of at least 0.2; and no life-threatening adverse events related to PE or its treatment through 30 days after the start of the APT procedure.

  2. Change From Baseline in RV/LV at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph [ Time Frame: Baseline (Day -2 [within -48 hrs of APT start]), Day 0 (within 4 hours after APT end), Day 2 (48 [± 6] hrs of APT start), Day 30 (± 5 days), Day 90 (± 10 days) and Day 365 (± 14 days) ]
  3. Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph [ Time Frame: Baseline (Day -2 [within -48 hrs of APT start]), Day 0 (within 4 hours after APT end), Day 2 (48 [± 6] hrs of APT start), Day 30 (± 5 days), Day 90 (± 10 days) and Day 365 (± 14 days) ]
  4. Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph [ Time Frame: Baseline (Day -2 [within -48 hrs of APT start]), Day 0 (within 4 hours after APT end), Day 2 (48 [± 6] hrs of APT start), Day 30 (± 5 days), Day 90 (± 10 days) and Day 365 (± 14 days) ]
  5. Percentage of Participants With Collapse of the Inferior Vena Cava (IVC) With Respiration at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph [ Time Frame: Baseline (Day -2 [within -48 hrs of APT start]), Day 0 (within 4 hours after APT end), Day 2 (48 [± 6] hrs of APT start), Day 30 (± 5 days), Day 90 (± 10 days) and Day 365 (± 14 days) ]
  6. Change From Baseline in Thrombus Burden by Miller Score as Assessed by Pulmonary Arteriogram (PAgram) at Day 0 [ Time Frame: Baseline, Day 0 (within 4 hours after APT end) ]
    Miller score is composed of a score for arterial obstruction (objective score) and a score for reduction of peripheral perfusion of lungs (subjective evaluation). Right pulmonary artery (PA) is assigned 9 segmental arteries (3 to the upper, 2 to the middle, and 4 to the lower lobe), and left PA is assigned only 7 segmental arteries (2 to the upper, 2 to the lingula, and 3 to the lower lobe). Presence of segmental emboli, regardless of the degree of obstruction, is scored 1 point. Proximal emboli to the segmental level are scored a value equal to the number of segmental arteries arising distally. Maximal score of obstruction=16. Reduction of peripheral perfusion is scored by dividing each lung into upper, middle, and lower zones and by using a 4-point scale: 0=normal perfusion; 1=moderately reduced perfusion; 2=severely reduced perfusion; 3=no perfusion. Maximal score of reduced perfusion=18. Thus, the maximal Miller score =34. Higher Miller score=more thrombus burden.

  7. Change From Baseline in Thrombus Burden by Modified Miller Score as Assessed by CTA Scan at Day 0 [ Time Frame: Baseline, Day 0 (within 4 hours after APT end) ]
    Modified miller score quantifies thrombus burden on CTA scans. Each segmental pulmonary artery (9 on the right, 7 on the left) that is fully or partly occluded by thrombus is given a score of 1. Any further proximal involves vessels score the number of segmental branches distal to that vessel, thereby giving a modified miller score of 0 (no thrombus) to 16 (thrombus in all segmental arteries or saddle embolism).

  8. Change in 6 Minute Walk (6MW) Distance From Day 30 to Day 90 and 365 [ Time Frame: Days 30, 90, 365 ]
    The 6 minute Walk Test is a measure of functional exercise capacity. Participants will be asked to walk as far as possible within a 6-minute period, and the distance covered at the end will be noted and recorded.

  9. Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365 [ Time Frame: Days 30, 90, and 365 ]
    Borg is a 10-point scale rating the maximum level of dyspnea (difficulty in breathing) and fatigue experienced before and after the 6MW distance test. Scores ranges from 0 (for no shortness of breath, or no fatigue) to 10 (for the greatest shortness of breath ever experienced, or maximum amount of fatigue felt). Higher scores indicates worse outcome.

  10. Number of Participants Who Received Oxygen Therapy [ Time Frame: Days 30, 90, and 365 ]
    Oxygen source is categorized as room air, nasal prongs, mask, and intubated.

  11. Change in Participant Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) 6b Score From Day 30 to Day 365 [ Time Frame: Day 30, Day 365 ]
    PROMIS-PF 6b questionnaire is developed by including 2-items from item-improved Health Assessment Questionnaire (HAQ) and 4-items from item-improved Physical Function-10 (PF-10) instruments. Both of these instruments assess participant's present abilities. Both "Item-Improved instruments" have 5-response options: HAQ - 1="without any difficulty," 2="with a little difficulty," 3="with some difficulty," 4="with much difficulty," 5="unable to do"; PF-10 - 1="not at all," 2="very little," 3="somewhat," 4="quite a lot," 5="cannot do." Total score is the average of all scores of component items, which ranges from 0 (no disability) to 100 (worst disability).

  12. Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Score From Day 30 to Day 365 [ Time Frame: Day 30, Day 365 ]
    The PEmb-QoL questionnaire contains 6 dimensions that has been created based on the contents of the items, frequency of complaints (Question [Q]1; score range: 1 [every day] to 5 [never]), activities of daily living (ADL) limitations (Q4; score range: 1 [limited a lot] to 3 [not at all]), work-related problems (Q5; response: yes/no), social limitations (Q6; score range: 1 [not at all] to 5 [extremely]), intensity of complaints (Q7 [pain in chest/shoulders]/8 [breathlessness]; score range: 1 [none] to 6 [very serious]) and emotional complaints (Q9; score range: 1 [at all times] to 6 [none of the times]). Total Score for all dimensions are calculated by the sum of the scores for each item of the dimension divided by the number of items. Total score ranges from 1 (better quality of life) to 100 (worst quality of life). Higher scores indicate poorer outcome (decreased quality of life). Questions 1, 4, 5, and 9 are reverse scored. Questions 2 and 3 provide descriptive information.

  13. Number of Participants Who Encountered Technical Procedural Complications [ Time Frame: Day 0 through Day 2 ]
    Technical complications associated with the use of the EKOS device will be recorded during catheter placement in the pulmonary artery and during the infusion procedure.

  14. Number of Participants With Symptomatic Recurrent Pulmonary Embolism (Per Adjudication Committee) [ Time Frame: From Baseline up to Day 365 ]
  15. Number of Participants Who Die Due to Any Cause [ Time Frame: From Baseline up to Day 365 ]
  16. For Participants of UK Sites: Number of Participants With Cardiovascular (CV) Collapse [ Time Frame: From Baseline up to Day 30 ]
    CV collapse was defined as one or more of the following: greater than (>) 40 millimeters of mercury (mmHg) drop in systolic blood pressure (SBP) (for >15 minutes from documented blood pressure as an in-patient) despite intravenous (IV) fluid challenge and absence of new atrial arrhythmia; Requirement for emergency systemic thrombolysis; Requirement for emergency surgical embolectomy ; Requirement for vasopressors; and Intubation/Ventilation.

  17. For Participants of UK Sites:Change in EuroQual - 5 Dimensions - 5 Levels (EQ-5D-5L) Score From Day 30 to Day 365 [ Time Frame: Day 30, Day 365 ]
  18. For Participants of UK Sites: Time From Hospital Admission to Diagnosis of PE [ Time Frame: From Baseline up to Day 3 ]
  19. For Participants of UK Sites: Time From Diagnostic Computed Tomography (CT) Scan to Initiation of Treatment for PE [ Time Frame: From Baseline up to Day 3 ]
  20. For Participants of UK Sites: Time in Each Level of Care (Level 0 and 1; Level 2; and/or Level 3) Through Discharge [ Time Frame: From Baseline up to Day 3 ]
    Levels are defined according to National Framework Document.

  21. For Participants of UK Sites: Number of Team Managing the Participant - Specialties Involved [ Time Frame: From Baseline up to Day 365 ]
  22. For Participants of UK Sites: Number of Healthcare Professionals (HCP) Visits for Venous Thromboembolism (VTE) [ Time Frame: From Day 30 up to Day 365 ]
  23. For Participants of UK Sites: Number of Hospital Re-Admission [ Time Frame: From Day 30 up to Day 365 ]
  24. For Participants of UK Sites: Duration of Hospital Re-Admission [ Time Frame: From Day 30 up to Day 365 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female greater than or equal to (≥) 18 years of age and less than or equal to (≤) 75 years of age.
  2. CTA evidence of proximal PE (filling defect in at least one main or lobar pulmonary artery).
  3. PE symptom duration ≤14 days.
  4. Submassive PE: RV/LV diameter ≥ 0.9 from CTA and hemodynamically stable.
  5. Must be treated within 48 hours of diagnosis of PE by CTA.
  6. Signed Informed consent obtained from subject or Legally Authorized Representative.

Exclusion Criteria:

  1. Stroke or transient ischemic attack (TIA), head trauma, or other active intracranial or intraspinal disease within one year.
  2. Recent (within one month) or active bleeding from a major organ.
  3. Major surgery within seven days of screening for study enrollment.
  4. Clinician deems the subject high-risk for catastrophic bleeding.
  5. History of heparin-induced thrombocytopenia (HIT).
  6. Catheter-based pharmacomechanical treatment for PE within 3 days of study enrollment.
  7. Systolic blood pressure (SBP) less than 90 mm Hg and/or use of vasopressors.
  8. Cardiac arrest (including pulseless electrical activity and asystole) requiring active cardiopulmonary resuscitation (CPR).
  9. Evidence of irreversible neurological compromise.
  10. Life expectancy < one year.
  11. Use of thrombolytics or glycoprotein IIb/IIIa antagonists within 3 days prior to inclusion in the study.
  12. Out-of-Range Laboratory Values: Hematocrit < 30%, Platelets < 100 thousand/microliter (μL), International normalized ratio (INR) > 3.
  13. Creatinine outside the normal range for the treating institution.
  14. Participant is pregnant (positive pregnancy test; women of childbearing capacity must be tested) or breast feeding.
  15. Active cancer (metastatic, progressive, or treated within the last 6 months). Exception: participants with non-melanoma primary skin cancers are eligible to participate in the study.
  16. Known allergy, hypersensitivity, or thrombocytopenia from heparin, r-tPA, or iodinated contrast except for mild-moderate contrast allergies for which steroid pre-medication can be used.
  17. History of any hematologic disease potentially involving abnormal platelet number or function.

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): NCT02396758


Locations
Show Show 21 study locations
Sponsors and Collaborators
EKOS Corporation
Investigators
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Principal Investigator: Victor Tapson, MD Cedar Sinai, Los Angeles

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Responsible Party: EKOS Corporation
ClinicalTrials.gov Identifier: NCT02396758    
Other Study ID Numbers: EKOS-12
2016-000502-11 ( EudraCT Number )
First Posted: March 24, 2015    Key Record Dates
Last Update Posted: September 30, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Pulmonary Embolism
Thrombosis
Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Plasminogen
Tissue Plasminogen Activator
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action