The primary objective of the study is to assess whether ultrasound-facilitated, catheter-directed, thrombolysis and anticoagulation are associated with a significant reduction in the composite outcome of PE-related mortality, cardiorespiratory…
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Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is a composite of PE-related mortality, cardiorespiratory
decompensation or collapse (as defined below), or non-fatal symptomatic and
objectively confirmed recurrence of PE, within seven (7) days of randomization.
Cardiorespiratory collapse or decompensation should fulfill at least one of the
following criteria:
a) cardiac arrest or need for CPR at any time between randomization and day 7;
b) signs of shock: new-onset persistent arterial hypotension (SBP below 90 mmHg
or SBP drop by at least 40 mmHg over at least 15 minutes, and despite an
adequate filling status; or need for vasopressors to maintain SBP of at least
90 mmHg), accompanied by end-organ hypoperfusion (altered mental status;
oliguria/anuria; or increased serum lactate) at any time between randomization
and day 7;
c) placement on ECMO at any time between randomization and day 7;
d) intubation, or initiation of non-invasive mechanical ventilation at any time
between randomization and day 7;
e) National Early Warning Score (NEWS) of 9 or higher, between 24 hours and 7
days after randomization, confirmed on consecutive measurements, taken twice.
Secondary outcome
1. Change in the RV-to-LV diameter ratio as measured by echocardiography
between baseline and 48±6 hours
2. PE-related death within 7 days;
3. Cardiorespiratory decompensation within 7 days;
4. Placement on ECMO or mechanical ventilation within 7 days;
5. GUSTO major (moderate and severe) bleeding within 7 days;
6. ISTH major bleeding within 7 days, 30 days, and 6 months;
7. Ischemic or hemorrhagic stroke within 7 days and 30 days;
8. All-cause mortality within 7 days, 30 days, 6 months, and 12 months;
9. Serious adverse events within 30 days;
10. All-cause mortality, cardiorespiratory collapse or recurrence of PE within
30 days;
11. Symptomatic PE recurrence within 30 days and 6 months;
12. Change from baseline in RV dysfunction on echocardiography at 6 months;
13. Duration of hospitalization for the index PE event;
14. Duration of stay at the intensive, intermediate or coronary care unit
during hospitalization for the index PE event;
15. Functional status at 30 days, 6 months, and 12 months, including:
a) WHO functional class (and discharge),
b) PVFS scale (and discharge),
c) 6-Minute Walk Test;
16. Quality of life (PEmb-QOL, SF-36, and EQ-5D scales) at 6 months and 12
months;
17. Diagnosis of CTEPH within 12 months;
18. Health economic analysis (length of hospital stay, resource utilization,
indirect costs) at 30 days and 12 months (selected sites and countries).
Background summary
Intravenously administered thrombolysis is the *prototype* of reperfusion
therapy for acute PE. Early studies reported significant hemodynamic
improvement after full-dose systemic thrombolysis, and a meta-analysis of 15
randomized controlled trials with a total of 2057 patients confirmed that
thrombolysis may improve early survival (odds ratio [OR] 0.59; 95% confidence
interval [CI] 0.36-0.96), and reduce PE-related death (OR 0.29; 95% CI
0.14-0.60) and recurrent PE (OR 0.50; 95% CI 0.27-0.94) compared to
anticoagulation alone (3). Today, PE guidelines recommend primary systemic
thrombolytic therapy only for *high-risk* patients with overt right ventricular
(RV) failure, i.e. those presenting with hemodynamic instability (4-6).
The majority of patients with acute PE appear hemodynamically stable at
presentation (7). However, patients with imaging or laboratory findings of RV
dysfunction may have an *intermediate* but still substantial (up to 8%) risk of
early death (7). It has been hypothesized that intermediate-risk patients may
benefit from early thrombolysis. In the randomized, placebo-controlled,
Pulmonary Embolism International Thrombolysis (PEITHO) trial, patients had
combined echocardiographic and laboratory evidence of RV dysfunction. All-cause
death or hemodynamic decompensation within 7 days was reduced in the
thrombolysis group, from 5.6% to 2.6% (OR 0.44; 95% CI 0.23-0.88). However,
this was offset by higher rates of hemorrhagic stroke (OR 12.10; 95% CI 1.57*
93.39) (8). High rates of major and intracerebral bleeding were confirmed by a
meta-analysis of thrombolysis trials, most of which employed systemic *full-
dose* thrombolysis (9).
Consequently, the current state of the art on thrombolysis for PE can be
summarized as follows:
a) Acute intermediate-risk (submassive) PE remains potentially life-threatening
when treated with anticoagulation alone.
b) Early reperfusion with standard-dose intravenous thrombolysis offers the
potential of improving hemodynamics as well as early clinical outcomes.
c) Reperfusion treatment is nevertheless not recommended for patients without
cardiogenic shock, because the bleeding risk of standard-dose thrombolytic
treatment is considered prohibitive.
This unsatisfactory situation, which deprives many patients with acute PE of a
potentially life-saving therapeutic option, can be resolved only if future
research focuses on the following key aspects:
a) Improve the safety of thrombolysis. Pharmacomechanical reperfusion, notably
ultrasound-facilitated catheter-directed thrombolysis (USCDT), has the
potential of reversing RV dilation, pulmonary hypertension, and anatomic
thrombus burden (10). In the randomized phase II Ultrasound Accelerated
Thrombolysis of Pulmonary Embolism Trial (ULTIMA), which enrolled 59 patients
with acute PE and a right-to-left ventricular dimension ratio > 1.0,
ultrasound-assisted local infusion of 10*20 mg recombinant tissue-type
plasminogen activator (r-tPA) led to significant recovery of RV function at 24
hours, with no increased risk of major hemorrhage or stroke (11). Supportive of
the efficacy and safety of this approach are also the results of (i) a
prospective, single-arm multicenter trial on 150 patients with submassive or
massive PE (12); (ii) a registry on catheter-directed, either purely mechanical
or pharmacomechanical thrombus removal including 28 patients with massive and
73 with submassive PE (13); and (iii) the prospective multicenter,
parallel-group optimum duration of acoustic pulse thrombolysis procedure in
acute intermediate-risk pulmonary embolism (OPTALYSE-PE) trial which randomized
101 hemodynamically stable adult patients, testing four USCDT regimens using a
shorter delivery duration for the primary efficacy endpoint defined as the
reduction in right ventricular*to*left ventricular diameter ratio by computed
tomographic angiography (14).
b) Advance the concept of intermediate-high risk and the PE severity criteria,
to better identify patients who may clinically benefit from thrombolysis. In
the PEITHO trial, baseline imaging and laboratory findings, but not clinical
parameters (apart from the requirement for hemodynamic *stability* at
presentation), were used as inclusion criteria (1). The combined primary
outcome and particularly early mortality rates were low both in the
thrombolysis and in the placebo (anticoagulant-only) arm (8). This generates
the hypothesis that better identification of *intermediate-high risk* PE may be
necessary to justify early thrombolysis. In a recent post-hoc analysis of the
PEITHO trial, baseline clinical variables were identified, which may be used
(in addition to RV dysfunction and troponin elevation) as additional criteria
to identify patients with an elevated risk of *imminent* hemodynamic
decompensation and an adverse early outcome (1). For the purpose of this
post-hoc analysis, the composite clinical outcome was defined as PE-related
death, hemodynamic collapse, or non-fatal symptomatic recurrent PE between
randomization and day 30. In the placebo arm, the rate of the composite
clinical outcome was 20% in patients with at least two clinical criteria of
severity, and this was reduced to 7.0% in the thrombolysis arm; this
corresponds to a relative risk reduction of 65%. In contrast, in patients who
fulfilled none of these clinical criteria, the rate of the composite clinical
outcome was only 2.3% in the placebo arm and higher, 3.8%, in the thrombolytic
arm. These findings must be regarded as exploratory and hypothesis-generating.
However, keeping in mind this limitation, they appear to support the
requirement for disease-specific clinical indicators of PE severity at
presentation on top of established imaging and biochemical criteria, to be used
as inclusion criteria in future trials testing safer reperfusion modalities in
intermediate-risk PE.
Study objective
The primary objective of the study is to assess whether ultrasound-facilitated,
catheter-directed, thrombolysis and anticoagulation are associated with a
significant reduction in the composite outcome of PE-related mortality,
cardiorespiratory decompensation or collapse, or non-fatal symptomatic and
objectively confirmed recurrence of PE compared to anticoagulation alone within
seven days of randomization.
Additional objectives are to contribute further evidence to the existing data
on the treatment and outcomes of acute, intermediate-high risk PE and to
provide controlled data comparing a catheter-based intervention to the standard
of care that is currently recommended in the guidelines.
Study design
The trial is a post-market, randomized, controlled, adaptive, open-label,
multicenter parallel-group trial with blinded adjudication of the primary
composite outcome. Subjects will be randomized 1:1 to treatment with USCDT and
anticoagulation or anticoagulation alone. The study is unblinded to
Investigators and subjects, but adjudication of the outcome measure and other
safety outcomes will be completed by a blinded CEC.
Initially, 406 subjects are planned to be enrolled at up to 65 sites in the US
and Europe. There will be a planned interim analysis after 50% are enrolled,
with the potential to enroll up to 544 subjects. The follow up period for each
subject is 12 months, so the overall study duration is anticipated to be at
least 36 months.
Subjects will be randomized 1:1 to receive either the USCDT intervention with
anticoagulation or will be treated with anticoagulation alone. Randomization
will be stratified by the following parameters:
* Age: <75 years vs *75 years
* RV/LV ratio on CTPA: <1.5 vs *1.5
Basic demographic, pseudonymized information about the subject will be entered
into the EDC. The research staff will confirm that all eligibility criteria are
met. The subject will be assigned a subject ID number and will receive a
randomized assignment to the USCDT treatment arm or anticoagulation-only
control arm. If they are assigned to receive USCDT, treatment should be
initiated as soon as practical, but no later than six (6) hours of confirmation
of diagnosis of intermediate-high risk PE. It is strongly recommended that it
begins within two hours of randomization.
Test (USCDT) Arm
Assignment to the USCDT arm will include both treatment with the USCDT
procedure and treatment with anticoagulation. The USCDT procedure will entail
delivery of alteplase using the EkoSonicTM Endovascular System. Alteplase will
be delivered using a specified treatment protocol (see section 10.3.4.1.1 for
the full protocol). Treatment must be initiated as soon as practical but no
more than six (6) hours after confirmation of diagnosis of intermediate-high
risk PE. It is strongly recommended that it begins within two (2) hours of
randomization.
Assignment to the experimental USCDT arm will also include initiation or
continuation of anticoagulation therapy according to a specified treatment
protocol. If a subject is already being treated with low molecular weight
heparin (LMWH) or unfractionated heparin (UFH), the treatment protocol for
continuation of therapy from the time of randomization is provided. See section
10.3.4.1.2.
Control (Anticoagulation) arm:
Assignment to the anticoagulation-only control arm will include either
initiation or continuation of anticoagulation therapy according to a specified
treatment protocol (see section 10.3.4.2 for the full protocol). Therapeutic
anticoagulation is the current standard of care in the treatment of acute
intermediate-high risk PE.
The control arm will not receive an interventional procedure. Note: there are
mechanisms in place if a subject requires an escalation in therapy with a
documented hemodynamic collapse or decompensation. In the absence of
hemodynamic collapse or decompensation, or documentation of such, institution
of any PE treatment beyond the therapy to which the subject was randomly
assigned will be considered a protocol deviation.
Intervention
Patients who fulfill all inclusion criteria and meet none of the exclusion
criteria will be enrolled in the study after providing written informed
consent. They will be randomized with a 1:1 ratio to ultrasound-facilitated,
catheter-directed thrombolysis (USCDT) combined with anticoagulation versus
anticoagulation alone.
Randomization and initiation of assigned therapy should follow as soon as
possible, but no more than six (6) hours after confirmation of diagnosis of
intermediate-high risk PE as defined by inclusion criteria #2-5. Randomization
should occur as soon as practical after the Investigator confirms diagnosis.
Initiation of assigned therapy should follow as soon as possible after
randomization. For subjects randomized to receive USCDT, it is strongly
recommended the intervention is initiated within two (2) hours of
randomization.
Study burden and risks
Risks associated with participation in this study are listed in the IFU and ICF.
Additional risks may exist. Risks can be minimized through compliance with the
protocol, performing procedures in the appropriate hospital environment,
adherence to subject selection criteria, close monitoring of the subject*s
physiologic status during research procedures and/or follow-ups and by promptly
supplying BSC with all pertinent information required by this protocol.
Data will be monitored as they are submitted to sponsor. Qualified employees at
sponsor, or a designee under contract, will conduct monitoring visits at the
initiation of the study and at interim intervals described in the monitoring
plan throughout the course of the study to evaluate protocol compliance and
determine if there are any issues that could affect the safety or welfare of
any subject in the study.
All study-specific tests and assessments completed by patients in the study are
considered part of routine care for patients with pulmonary embolism. Study
subjects may complete more questionnaires to assess symptoms and quality of
life, but they are not asked to undergo any procedures or examinations outside
standard care for this patient population.
However taking part in the study may be associated with a significant reduction
in the composite outcome of pulmonary embolism (PE)-related mortality,
cardiorespiratory decompensation or collapse, or nonfatal symptomatic and
objectively confirmed recurrence of PE.
300 Boston Scientific Way
Marlborough MA 01752
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Age
Inclusion criteria
1) Age 18-80 years, inclusive
2) Objectively confirmed acute PE, based on CTPA showing a filling defect in at
least one main or proximal lobar pulmonary artery (PA)
3) Elevated risk of early death/hemodynamic collapse, indicated by at least two
of the following new-onset clinical criteria:
i. Electrocardiogram (ECG)-documented tachycardia with heart rate *100 beats
per minute, not due to hypovolemia, arrhythmia, or sepsis;
ii. SBP * 110 mm Hg for at least 15 minutes;
iii. respiratory rate > 20 x min-1 or oxygen saturation on pulse oximetry
(SpO2) < 90% (or partial arterial oxygen pressure < 60 mmHg) at rest while
breathing room air;
4) Right-to-left ventricular (RV/LV) diameter ratio * 1.0 on CTPA
5) Serum troponin I or T levels above the upper limit of normal
6) Signed informed consent.
Exclusion criteria
1) Hemodynamic instability*, i.e. at least one of the following present:
a) cardiac arrest or need for cardiopulmonary resuscitation;
b) need for ECMO, or ECMO initiated before randomization
c) PE-related shock, defined as: (i) SBP < 90 mmHg, or vasopressors required to
achieve SBP * 90 mmHg, despite an adequate volume status; and (ii) end-organ
hypoperfusion (altered mental status; oliguria/anuria; increased serum lactate);
d) isolated persistent hypotension (SBP < 90 mmHg, or a systolic pressure drop
by at least 40 mmHg for at least 15 minutes), not caused by new-onset
arrhythmia, hypovolemia, or sepsis
* Patients who presented with temporary need for fluid resuscitation and/or
low-dose catecholamines may be included, provided that they could be stabilized
within 2 hours of admission and maintain
2) Need for admission to an intensive care unit for a reason other than the
index PE episode. Note: Patients who test positive for severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) can be enrolled where the investigator
believes that the pulmonary embolism is the dominant pathology in the patient*s
clinical presentation and qualifying cardiorespiratory parameters.
3) Temperature above 39oC / 102.2oF
4) Logistical reasons limiting the rapid availability of interventional
procedures to treat acute PE (e.g., during the outbreak of an epidemic)
5) Index PE symptom duration > 14 days
6) Active bleeding
7) History of intracranial or intraocular bleeding at any time
8) Stroke or transient ischemic attack within the past 6 months, or previous
stroke at any time if associated with permanent disability
9) Central nervous system neoplasm, or metastatic cancer
10) Major neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or
orthopedic surgery or trauma (including syncope-associated with head strike or
skeletal fracture) within the past 3 weeks
11) Platelet count < 100 x 109 x L-1
12) Patients who have received a once-daily therapeutic dose of LMWH or a
therapeutic dose of fondaparinux within 24 hours prior to randomization
13) Patients who have received one of the direct oral anticoagulants apixaban
or rivaroxaban within 12 hours prior to randomization
14) Patients who have received one of the direct oral anticoagulants dabigatran
or edoxaban for the index PE episode, as these drugs are not approved for
patients who have not received heparin for at least 5 days
15) Administration of a thrombolytic agent or a glycoprotein IIb/IIIa receptor
antagonist during the current hospital stay and/or within 30 days, for any
reason
16) Chronic treatment with antiplatelet agents other than low-dose
acetylsalicylic acid or clopidogrel 75 mg once daily (but not both). Dual
antiplatelet therapy is excluded.
17) Chronic treatment with a direct oral anticoagulant (apixaban, dabigatran,
edoxaban or rivaroxaban)
18) Chronic treatment with a vitamin K antagonist, or known coagulopathy
including severe hepatic dysfunction, with an International Normalized Ratio
(INR) > 1.5
19) Pregnancy or lactation
20) Previous inclusion in the study
21) Known hypersensitivity to alteplase, LMWH or UFH, or to any of the
excipients
22) Life expectancy less than 6 months
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT04790370 |
| CCMO | NL77735.041.21 |