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| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P050006 S060/ PAS001 |
| Date Original Protocol Accepted |
03/30/2018
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| Date Current Protocol Accepted |
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| Study Name |
Continued f/u of IDE Cohort
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| Device Name |
GORE CARDIOFORM Septal Occluder
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| General Study Protocol Parameters |
| Study Design |
Randomized Clinical Trial
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| Data Source |
Sponsor Registry
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| Comparison Group |
Concurrent Control
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| Analysis Type |
Analytical
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| Study Population |
Transit. Adolescent B (as adults) : 18-21 yrs,
Adult: >21
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| Detailed Study Protocol Parameters |
| Study Objectives |
The REDUCE study is a prospective, randomized (2:1), open-label, multi-center clinical study. The current post approval study is a continued follow-up of the premarket cohorts out to 5 years.
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| Study Population |
Enrollment in the REDUCE study was limited to patients who met the following key inclusion criteria:
Patient greater than or equal to 18 years and <60 years of age
Cryptogenic, ischemic stroke of presumed embolic etiology, verified by a neurologist within 180 days prior to randomization, meeting either criteria:
Ischemic stroke clinical symptoms persisting =24 hours; or
Clinical symptoms persisting <24 hours and MRI evidence of infarction.
For MRI-incompatible patients (i.e., patients that are claustrophobic and/or have implants that are contraindicated for MR), CT scan accepted
PFO, confirmed by TEE with bubble study demonstrating spontaneous right-to-left shunting or right-to-left shunting during Valsalva maneuver
Absence of an identifiable source of thromboembolism in the systemic arterial circulation.
Vascular imaging that rules out other potential sources of cerebral thromboembolism (e.g., dissection of the aorta or neck vessels, carotid stenosis >50% and/or presence of ulcerated plaques, or intracranial stenosis >50%)
No evidence of hypercoagulable state, which requires anticoagulation therapy, based on the evaluation of, at a minimum:
Platelet count, Prothrombin Time (PT) or INR, aPTT, and antiphospholipid antibodies.
A history of thromboembolic events in first degree family members obtained for all patients. For patients who had a first-degree family member with such an event prior to age 55, or whose family history is unknown, the following additional tests were required and must be interpreted as normal: Factor V Leiden mutation, Prothrombin Gene G20210A mutation, protein C, protein S, and Antithrombin III.
Testing for prothrombotic disorders may be performed at the discretion of the treating physicians but was not required.
Patients were randomized 2:1 to the test or the control group. Device group subjects were treated with antiplatelet medical management and PFO closure with the GORE® CARDIOFORM Septal Occluder or GORE® HELEX® Septal Occluder (prior device generation approved under P050006). Control group subjects were treated with antiplatelet medical management alone. Subjects at each site were treated with the same antiplatelet therapy regardless of study arm. Investigators chose one of the following options: aspirin alone (75-325 mg once daily), combination aspirin (50-100 mg) and dipyridamole (225-400 mg), or clopidogrel (75 mg once daily). Other combinations or the use of anticoagulants was not permitted.
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| Sample Size |
In the PMA study, 664 patients enrolled. There were 441 subjects randomized to the test group and 223 subjects randomized to the control group. The current post approval study is a continued follow-up of the premarket cohorts out to 5 years.
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| Key Study Endpoints |
Effectiveness Endpoints
With regards to effectiveness, there were two co-primary endpoints for the study. The first was freedom from recurrent clinical ischemic stroke through at least 24 months. A recurrent ischemic stroke event was defined as the first occurrence of one of the following:
• Clinical finding of ischemic stroke that may be associated with MRI evidence of a new relevant brain infarction. An ischemic stroke was defined as a neurological deficit, presumed due to ischemia, persisting longer than 24 hours or until death.
• Transient neurological deficit, presumed due to ischemia, persisting less than 24 hours that also had MRI evidence of a new relevant brain infarction.
The second co-primary endpoint was the incidence of subjects with new brain infarction or clinical findings of ischemic stroke from screening through 24 months or last follow-up visit, whichever occurred first. New brain infarction was defined as the composite of clinical ischemic stroke (defined above) or radiographically-detected but clinically covert brain infarct. Any subject with at least one new T2 hyperintense MRI lesion with diameter = 3 mm between the screening MRI and the 24-month MRI, or clinical findings of ischemic stroke through 24 months, and confirmed by the blinded MRI Core Lab or CEC, was classified as having a new brain infarction.
Secondary effectiveness endpoints consisted of an assessment of PFO closure in the device group subjects by transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE).
With regards to safety, endpoints included the proportion of subjects who experienced adverse events (AEs) that are determined to be related to device, procedure, and/or antiplatelet medical management. The safety assessment included specific adverse events and groups of adverse events such as all-cause adverse events, device-related events, procedure-related events, antiplatelet medical therapy-related events, and any serious adverse events.
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| Follow-up Visits and Length of Follow-up |
5 years
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
664 subjects were enrolled in this study at investigational sites in the United States, Canada and Europe with no persite
subject limit. 223 subjects were randomized to the Control Arm and 441 subjects were randomized to the Test
Arm. 331 subjects were enrolled at US sites with 216 randomized to the Test Arm and 115 randomized to the Control Arm.
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| Actual Number of Sites Enrolled |
A total of 63 investigational sites in the US, Canada and Europe enrolled subjects with 44 sites in just the US.
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| Patient Follow-up Rate |
87.3% (385/441) of subjects in the Test Arm completed the 5 year follow up visit. 78.9% (176/223) of subjects in
the Control Arm completed the 5 year follow up visit.
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| Final Safety Findings |
The safety endpoint included the proportion of subjects who experienced adverse events (AEs) that are determined to be
related to device, procedure, and/or antiplatelet medical management. The safety assessment included specific
adverse events and groups of adverse events such as all-cause adverse events, device-related events, procedure-related
events, antiplatelet medical therapy-related events, and any serious adverse events.
Overall, 28.6% (126/441) of subjects in the Test Arm and 30.9% (69/223) of subjects in the Control Arm had one or
more serious adverse events.
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| Final Effect Findings |
There were two co-primary endpoints for the study. The first was freedom from recurrent clinical ischemic stroke
through at least 24 months. A recurrent ischemic stroke event was defined as the first occurrence of one of the
following:
• Clinical finding of ischemic stroke that may be associated with MRI evidence of a new relevant brain
infarction. An ischemic stroke was defined as a neurological deficit, presumed due to ischemia,
persisting longer than 24 hours or until death.
• Transient neurological deficit, presumed due to ischemia, persisting less than 24 hours that also had
MRI evidence of a new relevant brain infarction.
Freedom from recurrent ischemic stroke or imaging confirmed TIA through 24 months was observed in 98.8%
of the Test Arm subjects and 95.2% of the Control Arm subjects. At 60 months post-procedure, freedom from
recurrent strokes was observed in 98.1% of the Rest Arm subjects and 94.1% of the Control Arm subjects.
The second co-primary endpoint was the incidence of subjects with new brain infarction or clinical findings of
ischemic stroke from screening through 24 months or last follow-up visit, whichever occurred first. New brain
infarction was defined as the composite of clinical ischemic stroke (defined above) or radiographically-detected but
clinically covert brain infarct. Any subject with at least one new T2 hyperintense MRI lesion with diameter = 3 mm
between the screening MRI and the 24-month MRI, or clinical findings of ischemic stroke through 24 months, and
confirmed by the blinded MRI Core Lab or CEC, was classified as having a new brain infarction.
Composite new brain infarction occurred in 23 subjects (6.0%) in the Test Arm and 20 subjects (11.3%) in the
Control Arm at 2 years.
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| Study Strengths & Weaknesses |
A strength of the study was that it provided results on the
long-term (5 years) safety and efficacy of the device.
A weakness of study was that there was no pre-specified,
quantitative safety endpoint.
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| Recommendations for Labeling Changes |
A labeling change is recommended to add the long-term
safety and efficacy results from the Post Approval Study
cohort.
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