Patent Foramen Ovale, Stroke, Transient Ischemic Attack (TIA)
Conditions
Keywords
PFO Closure, Cocoon PFO Occluder, Amplatzer PFO Occluder, Patent Foramen Ovale, Cryptogenic Stroke, Transient Ischemic Attack
Brief summary
This study is a prospective, multicenter, randomized, controlled, single-blind, investigator-driven, non-profit clinical trial designed to compare the safety and efficacy of the Cocoon PFO Occluder with the Amplatzer PFO Occluder family in patients requiring percutaneous closure of a patent foramen ovale (PFO). Eligible participants are adults with a history of cryptogenic embolic stroke or neurologically confirmed transient ischemic attack (TIA) within the previous 12 months and a PFO suitable for transcatheter closure. A total of up to 1260 subjects will be enrolled across multiple European centers. Participants will be randomly assigned in a 3:1 ratio to receive either the Cocoon PFO Occluder (experimental group) or an Amplatzer PFO closure device (control group). The procedure will be performed as soon as possible after randomization, preferably within 14 days and no later than 45 days. The primary endpoint is a non-inferiority comparison of a composite outcome at 12 months, including recurrent ischemic stroke, TIA, or all-cause death. Secondary endpoints include PFO closure rate at 6 months, assessed by echocardiographic imaging, and other measures of safety, device performance, and clinical outcomes. The study is conducted in a single-blind fashion: patients will not be informed of the device they receive unless they explicitly request this information. Any patient who chooses to be unblinded will continue to participate without affecting eligibility or follow-up, and the date of unblinding will be documented to allow appropriate sensitivity analyses. This trial aims to provide robust comparative evidence on the clinical performance of the Cocoon PFO Occluder relative to the Amplatzer PFO Occluder to guide optimal device selection in patients with cryptogenic stroke or TIA associated with PFO.
Interventions
DEVICEPFO Closure procedure
Percutaneous PFO closure performed according to standard clinical practice. The procedure is scheduled within 45 days after randomization and includes initiation of dual antiplatelet therapy before the intervention. Closure is performed following the Instructions for Use (IFU) of the assigned device and is guided by intracardiac echocardiography or transesophageal echocardiography. After device implantation, patients undergo routine post-procedure assessment and are instructed to follow antiplatelet therapy consistent with European clinical practice guidelines. Endocarditis prophylaxis is recommended for six months. The procedural steps are identical for both study arms; the only difference is the device implanted (Cocoon PFO Occluder or Amplatzer PFO Occluder). Participants are assigned to the two study arms using a 3:1 randomization scheme (Cocoon PFO Occluder : Amplatzer PFO Occluder).
Sponsors
Giuseppe Tarantini
Sahajanand Medical Technologies Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
The study is single-blind. Participants are masked to the device used (Cocoon vs. Amplatzer). Treating physicians and study staff involved in the procedure are not blinded due to the nature of the intervention. Participants may request unblinding at any time
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients with \>18 years of age and \<65 years of age, regardless of gender * Patients with normal or aneurysm type PFO confirmed by imaging examination \[Transthoracic Echocardiography (TTE)/ Transesophageal Echocardiography (TOE) or Intracardiac Echocardiography\], and who exhibit spontaneous right-to-left shunting or right-to-left shunting during Valsalva maneuver. * Patients with history of cryptogenic embolic stroke or transient ischemic attack in the previous 12 months \[stroke is defined as acute focal neurological deficit presumed to be due to focal ischemia, and either 1) symptoms persisting 24 hours or greater, or 2) symptoms persisting less than 24 hours but associated with MR or CT findings of a new, neuroanatomically relevant, cerebral infarct. Transient Ischemic Attack is defined as acute focal neurological deficit (defined as focal motor deficit, aphasia, difficulty walking, hemisensory deficit, amaurosis fugax, blindness, or focal visual deficit) presumed due to focal ischemia, lasting between 5 minutes and 24 hours, that is not associated with MR or CT findings of a new cerebral infarct\]. The diagnosis of cryptogenic embolic stroke or TIA has to be confirmed by a neurologist. * The size of PFO must be amenable to selection of a Cocoon PFO Occluder or Amplatzer PFO closure device. * Patients are informed of the nature of the trial and agree to all requirements for participation in the trial, signed the informed consent form, and agreed to complete the follow-up and follow-up examination
Exclusion criteria
* Patients who have definite causes of stroke or transient ischemic attack unrelated to the PFO * RLS caused by other causes, such as atrial septal defect or pulmonary arteriovenous shunt * Patients with atrial fibrillation/atrial flutter (chronic or intermittent) Intracardiac thrombus or tumor * Patients with mitral or aortic valve stenosis or severe regurgitation * Mitral or aortic valve vegetation or prosthesis * Active endocarditis or other untreated infectious diseases * Dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy * Left ventricular ejection fraction (LVEF) \<35% * Left ventricular aneurysm or akinesis Myocardial infarction or unstable angina pectoris within 12 months * Previous intracardiac surgery or percutaneous PFO-closure * Atherosclerosis or arteriopathy of intra- or extracranial vessels with \>50% diameter stenosis in the artery supplying the infarcted territory. * Patients with non-embolic cryptogenic stroke (for example lacunar stroke) or with other identifiable causes of stroke, including but not limited to aortic arch plaques (protruding \>4 mm into the lumen), large artery atherosclerotic disease, an established cardioembolic source, small-vessel occlusive disease, or arterial dissection * Glomerular filtration rate \< 30 ml/min/1.73 m2 or with any history of renal dialysis or renal transplantation * Severe liver function impairment (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal value） * Severe pulmonary disease including pulmonary hypertension (clinical diagnosis) * Uncontrollable hypertension or diabetes mellitus * Contraindications to anticoagulants or antiplatelet drugs, either before or after the PFO closure procedure * Active or planned (within 12 months) pregnancy, or lactating female patients * Patients with hypercoagulable states * Patients diagnosed with a neurological disease that causes progressive neurological dysfunction * Malignant tumors or other serious diseases resulting in a life expectancy of less than 12 months * Anatomy in which the device would interfere with intracardiac or vascular structures * Psychiatric conditions that may interfere with medical compliance and compliance with follow-up * Patient is currently participating in another investigational drug or device study that has not reached its primary endpoint yet * Patient with any medical condition that would make him/her inappropriate for treatment as per the current IFU of respective devices or in the opinion of the Investigator * Inability to obtain Informed Consent from patient or legally authorized representatives * Stroke with poor outcome at time of enrollment (Modified Rankin score \>3) * Subjects who will not be available for follow up for the duration of the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite endpoint of recurrent ischemic stroke, TIA, or all-cause death at 12 months | 12 months after the procedure | A non-inferiority comparison between the Cocoon PFO Occluder and the Amplatzer PFO Occluder in terms of a composite endpoint including: 1. Recurrent ischemic stroke, defined as an acute focal neurological deficit presumed to result from focal ischemia, with symptoms lasting ≥24 hours, or \<24 hours if accompanied by MRI or CT evidence of a new, anatomically relevant cerebral infarct. 2. Transient ischemic attack (TIA), defined as an acute focal neurological deficit (e.g., focal motor deficit, aphasia, gait disturbance, hemisensory deficit, amaurosis fugax, blindness, or focal visual deficit) presumed due to focal ischemia, lasting between 5 minutes and 24 hours, and not associated with MRI or CT evidence of a new infarct. Clinical evaluation by a neurologist is required. 3. All-cause mortality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFO Closure Rate | 6 months | Complete closure is defined as right-to-left shunt (RLS) grade 0. Effective closure is defined as RLS grade 0 or 1 on imaging (TTE as default, TOE when clinically indicated) |
| Composite of Recurrent Ischemic Stroke, TIA, or Death | 30 days and 6 months | Composite endpoint including recurrent ischemic stroke, TIA (neurologist-confirmed), or all-cause mortality. |
| Neurological Death | 30 days, 6 months, 12 months | Death attributable to neurological causes. |
| Cardiovascular Death | 30 days, 6 months, 12 months | Death attributable to cardiovascular causes. |
| Recurrent Symptomatic Non-Fatal Stroke | 30 days, 6 months, 12 months | TIA defined according to the same criteria as the primary endpoint and confirmed by a neurologist |
| Serious Adverse Events (SAE) | 30 days, 6 months, 12 months | Incidence of any serious adverse event as defined by standard reporting criteria. |
| Device- or Procedure-Related Serious Adverse Events | 30 days, 6 months, 12 months | SAE related to the device or procedure, including but not limited to: death, systemic embolism, device embolization or malposition, device thrombosis, cardiac injury/perforation, pericardial tamponade/effusion, endocarditis, atrial fibrillation, and severe vascular access complications |
| Clinically Significant New Atrial Arrhythmia | 30 days, 6 months, 12 months | New atrial arrhythmia (including AF) confirmed by ECG, Holter, or approved monitoring device. AF defined per international guidelines (≥30-second episode with absence of P waves and irregular RR intervals). |
| Device Success | Immediately after the procedure | Successful delivery, deployment at intended site, and retrieval of the delivery system. |
| Procedural Success | At hospital discharge | Device success without device- or procedure-related SAE prior to discharge |
| Change in Monthly Migraine Days | Months 9-12 vs. baseline (3 months before implantation) | Change in monthly migraine days in patients with a neurologist-confirmed diagnosis of migraine. |
| Quality of Life (SF-36 Score) | 6 months, 12 months | Assessment of quality of life using the SF-36 questionnaire. |
| Systemic Embolism | 30 days, 6 months, 12 months | Incidence of systemic embolic events confirmed clinically or by imaging |
| Possible/Probable Device-Related Allergy | 12 months | Device-related allergic reactions adjudicated by the Clinical Events Committee (CEC) |
| Echocardiographic Markers of Device Endothelialization | At 6 months (±1 month) post-procedure At 12 months (±2 months) post-procedure Additional TOE as clinically indicated through study completion (up to 12 months) | Evaluation of endothelialization using surrogate TOE markers: device surface echogenicity, peri-device flow, presence of thrombus/mass, visible disc surface area, and bubble contrast washout. Data will be summarized as the proportion of participants meeting criteria for complete endothelialization at each follow-up time point. |
Contacts
CONTACTDaniela Ramaccini, PhD, PharmaD
CONTACTFrancesco Cardaioli, MD
PRINCIPAL_INVESTIGATORGiuseppe Tarantini, MD, PhD, FESC
University of Padova
Outcome results
None listed