Clinical trial NCT02396758: Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism
Official title: Study of the OPTtimum Duration of Acoustic Pulse ThromboLYSis ProcEdure in the Treatment of Acute Submassive Pulmonary Embolism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Embolism and Thrombosis
Lead sponsor: Boston Scientific Corporation
Sponsor class: INDUSTRY
Collaborators: name: EKOS Corporation
First posted: 2015-03-24
Enrollment: 131
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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. For Participants in UK Sites: Submassive PE: RV/LV diameter ≥ 0.9 from CTA, hemodynamically stable and an elevated biomarker.
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. For Participants in UK Sites: Life expectancy \< one year or enrollment in hospice care.
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.

Primary outcomes:
measure: 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
timeFrame: Change from Baseline to 48 hrs ± 6 hours
measure: Number of Participants With Major Bleeding Within 72 Hours After Initiating the APT Procedure
timeFrame: Day 3 (within 72 hours after initiating the APT procedure)
Secondary outcomes:
measure: Percentage of Participants With Treatment Success of an APT Procedure
timeFrame: From Baseline up to Day 30
measure: Change From Baseline in RV/LV at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph.
timeFrame: 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)
measure: Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph
timeFrame: 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)
measure: Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Change From Baseline in Thrombus Burden by Miller Score as Assessed by Pulmonary Arteriogram (PAgram) at Day 0
timeFrame: Baseline, Day 0 (within 4 hours after APT end)
measure: Change From Baseline in Thrombus Burden by Modified Miller Score as Assessed by CTA Scan at 48 ± 6 Hours After the Start of the APT Procedure
timeFrame: From Baseline to 48 hrs ± 6 hours
measure: Change in 6 Minute Walk (6MW) Distance From Day 30 to Day 90 and 365
timeFrame: Days 30, 90, 365
measure: Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365
timeFrame: Days 30, 90, and 365
measure: Number of Participants Who Received Oxygen Therapy
timeFrame: Days 30, 90, and 365
measure: Change in Participant Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) 6b Score From Day 30 to Day 365
timeFrame: Day 30, Day 365
measure: Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Score From Day 30 to Day 365
timeFrame: Day 30, Day 365
measure: Number of Participants Who Encountered Technical Procedural Complications
timeFrame: From device placement through Day 2
measure: Number of Participants With Symptomatic Recurrent Pulmonary Embolism (Per Adjudication)
timeFrame: From Baseline up to Day 365
measure: Number of Participants Who Die Due to Any Cause
timeFrame: From Baseline up to Day 365
measure: For Participants of UK Sites: Freedom From Major Harm Occurring Between Enrolment and 30 Days
timeFrame: From Baseline up to Day 30
measure: For Participants of UK Sites:Change in EuroQual - 5 Dimensions - 5 Levels (EQ-5D-5L) Score From Day 30 to Day 365
timeFrame: Day 30, Day 365
measure: For Participants of UK Sites: Time From Hospital Admission to Diagnosis of PE
timeFrame: From Baseline through Day 3
measure: For Participants of UK Sites: Time From Diagnostic Computed Tomography (CT) Scan to Initiation of Treatment for PE
timeFrame: From Baseline through Day 3
measure: For Participants of UK Sites: Time in Each Level of Care (Level 0 and 1; Level 2; and/or Level 3) Through Discharge
timeFrame: From Baseline up to Hospital Discharge
measure: Healthcare Resource Utilization: Team Managing the Participant During Hospitalization - Number of Healthcare Professional (HCP) Specialties Involved. (UK Participants Only)
timeFrame: From Baseline up to Day 365
measure: Healthcare Resource Utilization: Number of Healthcare Professionals (HCP) Visits for Venous Thromboembolism (VTE) After Hospitalization and During 12month Follow-up. (UK Participants Only)
timeFrame: From Day 30 up to Day 365
measure: Healthcare Resource Utilization: Number of Healthcare Professionals (HCP) Visits for Venous Thromboembolism (VTE) After Hospitalization and During 12 Month Follow-up. (UK Participants Only)
timeFrame: From Day 30 up to Day 365
measure: Healthcare Resource Utilization: Number of Hospital Re-Admissions After Hospitalization and During 12 Month Follow-up. (UK Participants Only)
timeFrame: From Day 30 up to Day 365
measure: Healthcare Resource Utilization: Duration of Hospital Re-Admissions After Hospitalization and During 12 Month Follow-up. (UK Participants Only)
timeFrame: From Day 30 through Day 365
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Cedars Sinai
state: California
city: Tallahassee
country: United States
facility: Tallahassee Memorial Hospital
state: Florida
city: Tampa
country: United States
facility: Florida Hospital Tampa
state: Florida
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Augusta
country: United States
facility: University Hospital
state: Georgia
city: Indianapolis
country: United States
facility: St. Vincent Medical Group
state: Indiana
city: Louisville
country: United States
facility: Jewish Hospital
state: Kentucky
city: Metairie
country: United States
facility: East Jefferson General Hospital
state: Louisiana
city: Detroit
country: United States
facility: Detroit Medical Center
state: Michigan
city: Columbus
country: United States
facility: Mount Carmel Health System
state: Ohio
city: Erie
country: United States
facility: UPMC Hamot
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Richmond
country: United States
facility: Houston Methodist Sugarland Hospital
state: Texas
city: Alexandria
country: United States
facility: Inova Alexandria Hospital
state: Virginia
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center
state: Washington
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
state: England
city: Gillingham
country: United Kingdom
facility: Medway Maritime Hospital
state: England
city: London
country: United Kingdom
facility: Royal Free Hospital
state: England
city: London
country: United Kingdom
facility: St. Thomas Hospital
state: England
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
state: Scotland
Study officials:
affiliation: Cedar Sinai, Los Angeles
name: Victor Tapson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Piazza G, Sterling KM, Tapson VF, Ouriel K, Sharp ASP, Liu PY, Goldhaber SZ. One-Year Echocardiographic, Functional, and Quality of Life Outcomes After Ultrasound-Facilitated Catheter-Based Fibrinolysis for Pulmonary Embolism. Circ Cardiovasc Interv. 2020 Aug;13(8):e009012. doi: 10.1161/CIRCINTERVENTIONS.120.009012. Epub 2020 Aug 6.
citation: 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.