Stroke, Transient Ischemic Attack
Conditions
Keywords
cryptogenic, stroke, transient ischemic attack, TIA, PFO, Patent foramen ovale, HELEX, Septal Occluder, PFO Occluder
Brief summary
The primary objective is to determine if patent foramen ovale (PFO) closure with the GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder plus antiplatelet medical management is safe and effective and reduces the risk of recurrent stroke or imaging-confirmed transient ischemic attack (TIA) when compared to antiplatelet medical management alone in patients with a PFO and history of cryptogenic stroke or imaging-confirmed TIA. A co-primary objective is to demonstrate that medical management plus closure with the study device reduces the risk of new brain infarct compared to medical management alone.
Interventions
DEVICESeptal Occluder Device
PFO closure with study septal occluder device
DRUGAntiplatelet Medical Therapy
Investigator's choice of one of three regimen options specified in protocol
Sponsors
W.L.Gore & Associates
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Presence of cryptogenic ischemic stroke or TIA of presumed embolic infarction verified by a neurologist within 180 days prior to randomization * Presence of Patent Foramen Ovale (PFO), as determined initially by positive bubble study utilizing transesophageal echocardiography (TEE), demonstrating spontaneous right-to-left shunting or right-to-left shunting during Valsalva maneuver. * Absence of an identifiable source of thromboembolism in the systemic circulation * No evidence of a hypercoagulable state * Note: Additional Inclusion Criteria may apply
Exclusion criteria
* Other co-morbidities including, but not limited to, mural thrombus, dilated cardiomyopathy, atrial fibrillation/flutter, cardiac prosthetics (valves), mitral valve stenosis, aortic dissection, significant atherosclerosis, vasculitis, pre-existing neurologic disorders, multiple sclerosis, arteriovenous malformations, prior intracranial hemorrhage, severe central nervous system (CNS) disease, severe disability related to prior stroke, and autoimmune disorders that would increase the risk of mortality or morbidity above what is typical for the treatment * Previous Myocardial Infarction * Active infection that cannot be treated successfully prior to randomization * Sensitivity or contraindication to all proposed medical treatments * Pregnancy or intent on becoming pregnant through 24-months after randomization * Indications outside the parameters accepted for placement of the GORE® HELEX® Septal Occluder / GORE® Septal Occluder, including extensive congenital cardiac anomalies and defect diameter estimated to be \> 18mm * Atrial septal anatomy that is expected to necessitate placement of more than one GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder * Need for concomitant procedure(s) that may confound detection of adverse events related to device placement * Note: Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Freedom From Recurrent Ischemic Stroke (Primary Outcome #1) | 24 months | A recurrent stroke event was defined as the first occurrence post-randomization of either a) neurological deficit presumed due to ischemia and persisting longer than 24 hours or until death, or b) transient neurological deficit presumed due to ischemia, persisting less than 24 hours with MRI evidence of a new relevant brain infarction. |
| Number of Subjects With New Brain Infarct or Recurrent Stroke (Primary Outcome #2) | 24 months | Responders were subjects who showed one or more new infarctions on MRI since screening, or experienced a confirmed recurrent stroke, through 24 months (913 days). Nonresponders were subjects who did not show new infarction on MRI since screening and were confirmed free of recurrent stroke through at least 549 days. An infarction was defined as a new (since screening) T2 hyperintense MRI lesion with diameter ≥ 3 mm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Study-related Serious Adverse Events | 24 months | Adverse event seriousness and relationship to study treatments (device, procedure, or antiplatelet medical therapy) as reported by each investigative site |
| Number of Subjects With Effective Closure in Test (Device) Arm | 24 months | Assessment of PFO closure in test (device) arm subjects by transesophageal echocardiography (TEE) at 24-month follow-up. Effective closure defined as occluded, small, or moderate shunt (0-25 bubbles). |
Countries
Denmark, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Device Closure PFO closure with study septal occluder device plus antiplatelet medical therapy
Septal Occluder Device: GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder
Antiplatelet Medical Therapy: Investigator's choice of one of three regimen options specified in protocol | 441 |
| Medical Management Antiplatelet medical therapy alone
Antiplatelet Medical Therapy: Investigator's choice of one of three regimen options specified in protocol | 223 |
| Total | 664 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Lost to Follow-up | 23 | 13 |
| Overall Study | Physician Decision | 4 | 5 |
| Overall Study | Withdrawal by Subject | 10 | 15 |
Baseline characteristics
| Characteristic | Device Closure | Medical Management | Total |
|---|---|---|---|
| Age, Continuous | 45.4 years STANDARD_DEVIATION 9.3 | 44.8 years STANDARD_DEVIATION 9.6 | 45.2 years STANDARD_DEVIATION 9.4 |
| Atrial septal aneurysm | 86 Participants | — | 86 Participants |
| Current smoking | 63 Participants | 25 Participants | 88 Participants |
| Diabetes mellitus | 18 Participants | 10 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 9 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 413 Participants | 213 Participants | 626 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 7 Participants |
| Hypertension | 112 Participants | 58 Participants | 170 Participants |
| Index event Stroke symptoms <24 hr, w/ imaging confirmation | 39 Participants | 24 Participants | 63 Participants |
| Index event Stroke w/ symptoms >=24 hr | 402 Participants | 199 Participants | 601 Participants |
| Patent foramen ovale shunt size Large (>25 bubbles) | 182 Participants | 79 Participants | 261 Participants |
| Patent foramen ovale shunt size Moderate (6-25 bubbles) | 166 Participants | 94 Participants | 260 Participants |
| Patent foramen ovale shunt size Small (1-5 bubbles) | 77 Participants | 43 Participants | 120 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 12 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 5 Participants | 15 Participants |
| Race (NIH/OMB) White | 412 Participants | 203 Participants | 615 Participants |
| Region of Enrollment Canada | 17 Participants | 8 Participants | 25 Participants |
| Region of Enrollment Denmark | 79 Participants | 38 Participants | 117 Participants |
| Region of Enrollment Finland | 18 Participants | 8 Participants | 26 Participants |
| Region of Enrollment Norway | 25 Participants | 14 Participants | 39 Participants |
| Region of Enrollment Sweden | 64 Participants | 31 Participants | 95 Participants |
| Region of Enrollment United Kingdom | 22 Participants | 9 Participants | 31 Participants |
| Region of Enrollment United States | 216 Participants | 115 Participants | 331 Participants |
| Sex: Female, Male Female | 180 Participants | 85 Participants | 265 Participants |
| Sex: Female, Male Male | 261 Participants | 138 Participants | 399 Participants |
| Stroke or TIA before index event Previous either | 62 Participants | 23 Participants | 85 Participants |
| Stroke or TIA before index event Previous stroke | 42 Participants | 13 Participants | 55 Participants |
| Stroke or TIA before index event Previous TIA | 26 Participants | 11 Participants | 37 Participants |
| Time from qualifying event to randomization | 100 days STANDARD_DEVIATION 52 | 101 days STANDARD_DEVIATION 53 | 101 days STANDARD_DEVIATION 53 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 441 | 0 / 223 |
| other Total, other adverse events | 324 / 441 | 154 / 223 |
| serious Total, serious adverse events | 102 / 441 | 62 / 223 |
Outcome results
Primary
Number of Subjects With Freedom From Recurrent Ischemic Stroke (Primary Outcome #1)
A recurrent stroke event was defined as the first occurrence post-randomization of either a) neurological deficit presumed due to ischemia and persisting longer than 24 hours or until death, or b) transient neurological deficit presumed due to ischemia, persisting less than 24 hours with MRI evidence of a new relevant brain infarction.
Time frame: 24 months
Population: Intention to Treat: includes all subjects randomized
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Device Closure | Number of Subjects With Freedom From Recurrent Ischemic Stroke (Primary Outcome #1) | 6 Participants |
| Medical Management | Number of Subjects With Freedom From Recurrent Ischemic Stroke (Primary Outcome #1) | 12 Participants |
Comparison: Test null hypothesis of equal or lower recurrent stroke-free survivorship for device closure compared to medical management.~H0: Sd(t) ≤ Sm(t) for all t, versus H1: Sd(t) \> Sm(t) for all t, where Sd(t) and Sm(t) are true Kaplan-Meier product-limit survivor functions for the device closure and medical management arms and t is time from randomization to event or censoring.~Event-free subjects were censored at time of last follow-up. Significance threshold (1-sided alpha) = 0.025.p-value: 0.00195% CI: [0.09, 0.62]Log Rank
Primary
Number of Subjects With New Brain Infarct or Recurrent Stroke (Primary Outcome #2)
Responders were subjects who showed one or more new infarctions on MRI since screening, or experienced a confirmed recurrent stroke, through 24 months (913 days). Nonresponders were subjects who did not show new infarction on MRI since screening and were confirmed free of recurrent stroke through at least 549 days. An infarction was defined as a new (since screening) T2 hyperintense MRI lesion with diameter ≥ 3 mm.
Time frame: 24 months
Population: Intention to Treat: includes all subjects randomized and evaluated for brain infarct
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Device Closure | Number of Subjects With New Brain Infarct or Recurrent Stroke (Primary Outcome #2) | 22 Participants |
| Medical Management | Number of Subjects With New Brain Infarct or Recurrent Stroke (Primary Outcome #2) | 20 Participants |
Comparison: Test null hypothesis of equal or higher proportion with brain infarct for device closure compared to medical management.~H0: Pm - Pd ≤ 0, versus H1: Pm - Pd \> 0, where Pd and Pm are true proportions of subjects with brain infarct for the device closure and medical management arms.~Significance threshold (1-sided alpha) = 0.025.p-value: 0.02495% CI: [0.003, 0.108]z-test, 1-sided
Secondary
Number of Subjects With Effective Closure in Test (Device) Arm
Assessment of PFO closure in test (device) arm subjects by transesophageal echocardiography (TEE) at 24-month follow-up. Effective closure defined as occluded, small, or moderate shunt (0-25 bubbles).
Time frame: 24 months
Population: All subjects randomized to test (device) arm with 24-month PFO closure assessment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Device Closure | Number of Subjects With Effective Closure in Test (Device) Arm | 312 Participants |
Secondary
Number of Subjects With Study-related Serious Adverse Events
Adverse event seriousness and relationship to study treatments (device, procedure, or antiplatelet medical therapy) as reported by each investigative site
Time frame: 24 months
Population: Intention to Treat: all subjects randomized
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Device Closure | Number of Subjects With Study-related Serious Adverse Events | 102 Participants |
| Medical Management | Number of Subjects With Study-related Serious Adverse Events | 62 Participants |