Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism

Study of the OPTtimum Duration of Acoustic Pulse ThromboLYSis ProcEdure in the Treatment of Acute Submassive Pulmonary Embolism

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.

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.

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.