(121 days)
- The pRESET® Thrombectomy Device is indicated for use to restore blood flow in the neurovasculature by removing thrombus for the treatment of acute ischemic stroke to reduce disability in patients with a persistent, proximal anterior circulation, large vessel occlusion, and smaller core infarcts who have first received thrombolytic therapy. Endovascular therapy with the device should be started within 6 hours of symptom onset.
- The pRESET® Thrombectomy Device is indicated to restore blood flow by removing thrombus from a large intracranial vessel in patients experience stroke within 8 hours of symptom onset. Patients who are ineligible for thrombolytic therapy or who fail thrombolytic therapy are candidates for treatment.
The pRESET® Thrombectomy Device is designed to restore blood flow in the neurovasculature by mechanical removal of thrombus in patients experiencing acute ischemic stroke due to large vessel occlusion with thrombus. The device is designed for use in large vessels of the neurovasculature such as the internal carotid artery (ICA) and the middle cerebral artery (MCA). The device is supplied sterile and intended for single use only.
Here's a breakdown of the acceptance criteria and the study proving the device meets those criteria, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
| Acceptance Criteria (Endpoint) | Reported Device Performance (pRESET) (Intent-to-Treat Population) | Predicate Device (Solitaire) (Intent-to-Treat Population) | Difference (pRESET minus Solitaire) | 1-Sided 95% Confidence Interval (Lower, Upper Bound) | Met/Not Met (Based on Thresholds) |
|---|---|---|---|---|---|
| Primary Effectiveness: 90 Day mRS ≤ 2 (Proportion of subjects with global disability mRS ≤ 2 at 90 days after index procedure) | 95 (54.91%) | 96 (57.49%) | -2.57% | -11.42%, 6.28% | Met (Lower bound -11.42% > -12.5%) |
| Primary Safety: 24 Hour sICH (Proportion of subjects with device- or procedure-related symptomatic intracerebral hemorrhage within 24 hours) | 0 (0.00%) | 2 (1.20%) | -1.20% | -2.58%, 0.19% | Met (Upper bound 0.19% < 5%) |
| Secondary Effectiveness: eTICI ≥ 2b50 (Proportion of subjects with eTICI 2b50 or greater flow in target vessel post-procedure with ≤ 3 passes) | 146 (84.39%) | 149 (89.22%) | -4.83% | -10.84%, 1.19% | Met (Lower bound -10.84% > -12.1%) |
Note: The "Met/Not Met" column is inferred based on the stated "a priori threshold" for each criterion. The document explicitly states that the pRESET device was "demonstrated to be non-inferior" for these outcomes.
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size for Test Set:
- Intent-to-Treat (ITT) Population: 340 subjects (173 pRESET, 167 Solitaire)
- Per Protocol (PP) Population: 266 subjects (138 pRESET, 128 Solitaire)
- As Treated (AT) Population: 322 subjects (166 pRESET, 156 Solitaire)
- Data Provenance: Prospective, multicenter, randomized controlled clinical trial conducted across 24 sites in the US (n=19) and Germany (n=5).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts
The document does not explicitly state the number or qualifications of experts used to establish the ground truth for parameters like eTICI scores or mRS assessments. However, it's a clinical trial, implying that such assessments would be made by qualified medical professionals (e.g., neurologists, interventional neuroradiologists) at each of the 24 participating sites. The ground truth for neurological and functional evaluations, and imaging interpretations (e.g., ASPECTS, core infarct volume, eTICI), would have been established by these clinical trial personnel.
4. Adjudication Method for the Test Set
The document does not explicitly describe an adjudication method (like 2+1, 3+1) for the test set. In a multicenter clinical trial investigating medical devices, independent core labs or central adjudication committees are often used for key endpoints, especially for imaging and neurological outcomes, to ensure consistency and reduce bias. However, this level of detail is not provided in the summary.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study is a clinical trial comparing two thrombectomy devices (pRESET vs. Solitaire), not comparing human readers with and without AI assistance. The "readers" in this context would be the clinicians performing the procedures and assessing outcomes, not interpreting images for AI.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
No, this is a study of a physical medical device (thrombectomy device), not an algorithm or AI system. Therefore, no standalone algorithm performance study was relevant or performed.
7. The Type of Ground Truth Used
The ground truth used in the clinical trial includes:
- Clinical Outcomes Data: Modified Rankin Scale (mRS) at 90 days (patient disability), symptomatic intracerebral hemorrhage (sICH) within 24 hours.
- Angiographic Data: eTICI (Expanded Thrombolysis in Cerebral Infarction) scores indicating blood flow restoration.
- Imaging Data: ASPECTS score (visual assessment of ischemic changes on CT), core infarct volume (from MRI-DWI or CTP).
These are established by clinical assessments and imaging interpretations by medical professionals.
8. The Sample Size for the Training Set
The document describes a clinical trial (PROST) evaluating the pRESET Thrombectomy Device against the Solitaire Revascularization Device. This is a comparative effectiveness study, not a machine learning study. Therefore, there is no "training set" in the context of an algorithm or AI. The term "training set" is not applicable here.
9. How the Ground Truth for the Training Set was Established
As there is no training set for an AI/algorithm, this question is not applicable. The data collected was for a clinical trial to demonstrate safety and effectiveness, and the outcomes were assessed using standard clinical and imaging measures.
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January 20, 2023
Image /page/0/Picture/1 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
phenox Limited Catriona Lynch Regulatory Affairs Specialist Kamrick Court, Ballybrit Business Park. Galway H91 XY38, Ireland
Re: K222848
Trade/Device Name: pRESET Thrombectomy Device Regulation Number: 21 CFR 882.5600 Regulation Name: Neurovascular Mechanical Thrombectomy Device for Acute Ischemic Stroke Treatment Regulatory Class: Class II Product Code: POL, NRY Dated: December 16, 2022 Received: December 19, 2022
Dear Catriona Lynch:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal
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statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Naira Muradyan -S
Naira Muradyan, Ph.D. Assistant Director DHT5A: Division of Neurosurgical, Neurointerventional and Neurodiagnostic Devices OHT5: Office of Neurological and Physical Medicine Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health
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Indications for Use
510(k) Number (if known) K222848
Device Name pRESET Thrombectomy Device
Indications for Use (Describe)
-
The pRESET® Thrombectomy Device is indicated for use to restore blood flow in the neurovasculature by removing thrombus for the treatment of acute ischemic stroke to reduce disability in patients with a persistent, proximal anterior circulation, large vessel occlusion, and smaller core infarcts who have first received thrombolytic therapy. Endovascular therapy with the device should be started within 6 hours of symptom onset.
-
The pRESET® Thrombectomy Device is indicated to restore blood flow by removing thrombus from a large intracranial vessel in patients experience stroke within 8 hours of symptom onset. Patients who are ineligible for thrombolytic therapy or who fail thrombolytic therapy are candidates for treatment.
Type of Use (Select one or both, as applicable)X Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
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510(k) Summary (21 CFR 807.92)
K222848
I. SUBMITTER
phenox Limited, Kamrick Court Ballybrit Business Park, Galway, Ireland, H91 XY38.
| Primary Correspondent Name: | Catriona Lynch |
|---|---|
| Title: | Regulatory Affairs Specialist |
| Phone: | +353 91 740 100 |
| Email: | catriona.lynch@phenox.ie |
| Secondary Correspondent Name: | Gary Brogan |
| Title: | Managing Director |
Date Prepared: 20 January 2023
II. DEVICE
Phone:
Email:
Device Trade Name: pRESET® Thrombectomy Device Common or Usual Name: Neurovascular Mechanical Thrombectomy Device for Acute Ischemic Stroke Treatment; Catheter, Thrombus Retriever Classification: Class 2 device according to 21 CFR 882.5600; 21 CFR 870.1250 Product Code: POL, NRY Review Panel: Neurology
+353 91 740 100
III. PREDICATE DEVICE
Device Name: Solitaire™ 2 Revascularization Device, K162539. 510(k) Submitter: Micro Therapeutics, Inc. d/b/a ev3 Neurovascular
IV. DEVICE DESCRIPTION
The pRESET® Thrombectomy Device is designed to restore blood flow in the neurovasculature by mechanical removal of thrombus in patients experiencing acute ischemic stroke due to large vessel occlusion with thrombus. The device is designed for use in large vessels of the neurovasculature such as the internal carotid artery (ICA) and the middle cerebral artery (MCA). The device is supplied sterile and intended for single use only.
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Materials of Use: See table below for details of the materials used in the construction of the pRESET® Thrombectomy Device.
| Component | Material |
|---|---|
| Retrieval Structure | Nitinol |
| Push-Wire | Stainless Steel Wire |
| Connector Shell | Nitinol |
| Marker coils | Platinum/Iridium |
| Shrink Tubing | PTFE |
| Introducer Sheath | HDPE |
V. INDICATIONS FOR USE
Comparison of Indications for Use for the pRESET ®Thrombectomy Device and predicate device Solitaire™ 2 Revascularization Device.
| Parameter | Predicate Device | Subject Device |
|---|---|---|
| Indications for Use | 1. The Solitaire™ 2 RevascularizationDevice is indicated for use to restoreblood flow in the neurovasculatureby removing thrombus for thetreatment of acute ischemic stroketo reduce disability in patients witha persistent, proximal anteriorcirculation, large vessel occlusion,and smaller core infarcts who havefirst received intravenous tissueplasminogen activator (IV t-PA).Endovascular therapy with thedevice should be started within 6hours of symptom onset.2. The Solitaire™ RevascularizationDevice is indicated to restore bloodflow by removing thrombus from alarge intracranial vessel in patientsexperiencing ischemic stroke within8 hours of symptom onset. Patientswho are ineligible for IV t-PA or whofail IV t-PA therapy are candidatesfor treatment. | 1. The pRESET® Thrombectomy Deviceis indicated for use to restore bloodflow in the neurovasculature byremoving thrombus for the treatmentof acute ischemic stroke to reducedisability in patients with a persistent,proximal anterior circulation, largevessel occlusion, and smaller coreinfarcts who have first receivedthrombolytic therapy. Endovasculartherapy with the device should bestarted within 6 hours of symptomonset.2. The pRESET® Thrombectomy Deviceis indicated to restore blood flow byremoving thrombus from a largeintracranial vessel in patientsexperiencing ischemic stroke within 8hours of symptom onset. Patients whoare ineligible for thrombolytic therapyor who fail thrombolytic therapy arecandidates for treatment. |
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phenox
Traditional 510(k) pRESET® Thrombectomy Device
VI.COMPARISON OF TECHNOLOGICAL CHARACTERISTICS WITH THE PREDICATE DEVICE
| Parameter | Predicate Device | Subject Device |
|---|---|---|
| Trade Name | Solitaire™ 2 RevascularizationDevice | pRESET® Thrombectomy Device |
| 510(k) number | K162539 | K222848 |
| Product Classification | II | II |
| ClassificationRegulation | 21 CFR 882.5600,21 CFR 870.1250 | 21 CFR 882.5600,21 CFR 870.1250 |
| Product Code | POL, NRY | POL, NRY |
| Principle of Operation | The device is used in theneurovasculature to restore bloodflow for treatment of acuteischemic stroke. | The device is used in theneurovasculature to restore blood flowfor treatment of acute ischemic stroke. |
| Device Sizes | 4x15mm4x20mm4x40mm6x20mm6x30mm | 4x20mm5x40mm6x30mm |
| Materials | Retrieval Structure- NitinolMarkers- Platinum/IridiumPush Wire- NitinolShrink Tubing- PTFE | Retrieval Structure- NitinolMarkers- Platinum/IridiumPush Wire- Stainless SteelShrink Tubing- PTFE |
| Use | Sterile, Single Use | Sterile, Single Use |
| Sterilization Method | Ethylene Oxide | Ethylene Oxide |
| Packaging | Stored within dispenser coil,Tyvek pouch and shipping carton | Stored within dispenser coil,Tyvek pouch and shinning carton |
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VII. PERFORMANCE DATA
BIOCOMPATIBILITY
Biocompatibility testing was conducted based on International Organization for Standardization (ISO) 10993-1:2018: Biological Evaluation of Medical Devices - Part 1: Evaluation and testing within a risk management process and the US FDA guidance document "Use of International Standard ISO 10993, 'Biological Evaluation of Medical Devices - Part 1: Evaluation and testing within a risk management process" (2020). Results confirmed the pRESET® Thrombectomy Device is biocompatible.
| Biological Effects | Test names | Conclusions | |
|---|---|---|---|
| Cytotoxicity | ISO MEM elution –L929 fibroblast cultures | Non-cytotoxic | |
| Sensitization | ISO guinea pig maximization test | No sensitization indicated | |
| Skin Irritation | Rabbitprimary skin irritation/intracutaneous reactivity | No irritation indicated | |
| Systemic toxicity | Material mediated pyrogenicity test | Non-pyrogenic | |
| Systemic toxicity | Acute systemic toxicity | No acute systemic toxicity | |
| Hemocompatibility | Thromboresistance in dogs | Thromboresistant | |
| In vitro hemocompatibilityPartial thromboplastin time (PTT) | No Hemolysis indicated | ||
| Hemocompatibility | Hemolysis (ASTM method) directcontact | No Hemolysis indicated | |
| Hemocompatibility | Hemolysis (ASTM method) indirectextract | ||
| Hemocompatibility | Complement activation | No complement activation |
Table below summarizes testing performed on the pRESET® Thrombectomy Device.
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STERILIZATION
pRESET® Thrombectomy Device is sterilized by Ethylene Oxide gas. The sterilization cycle has been validated to ensure a sterility assurance level (SAL) of 10° in accordance with the EN ISO 11135:2014 & A1:2019 and AAMI TIR28:2016.
Aging studies have established the pRESET® Thrombectomy Device packaging remains functional and maintains sterility for up to 3 years. Aging studies for packaging integrity, seal strength and device functionality were performed and met acceptance criteria.
NON-CLINICAL PERFORMANCE DATA
Non-clinical testing was completed to support the substantial equivalence determination to the predicate. The tests are summarized below.
Performance Testing - Bench
The following bench testing was performed to support substantial equivalence.
| Test names | Test Description | Conclusions |
|---|---|---|
| Simulated Use | It shall be possible to safely and reliably prepare, deploy and retract the device in a nominal and worst-case 3D model as described in the instructions for use without damage to the device. | Pass |
| Dimensional Verification | Expanded outer diameter (OD)Retriever device lengthWorking length of retrieval deviceEffective length of retrieval deviceSystem lengthDiameter 10 mm from device connection pointDiameter 275 mm from device connection pointLength of uncovered markerMarker positionDiameter of heat shrink - device connection pointDiameter of distal marker coilsLength of distal marker coils | Pass |
| Radial Force | The relative Chronic Outward Force(RCOF) in the labeled vessel diametersmust meet acceptance criteria. | Pass |
| Radiopacity | Proximal and distal ends of the retrievaldevice must be radiopaque. | Pass |
| Kink Resistance | The PRESET device will not kink duringsimulated use in a nominal and worst-case 3D model following the instructionsfor use. | Pass |
| The PRESET stent region does not kink orcollapse while passing through a worst-case anatomical model incorporatingminimum bend radii. | Pass | |
| System Surface Finish | The external surface of the effectivelength of the device shall appear freefrom extraneous matter, process andsurface defects. | Pass |
| Ar Transition Temperature | Ar transition temperature of the PRESETdevice will be appropriate for clinicalusage. Test will use the bend and freerecovery method. | Pass |
| Device Deployment | It shall be possible to safely and reliablydeploy the device as described in theinstructions for use without damage tothe device. | Pass |
| Retraction into theMicrocatheter | It shall be possible to advance arepresentative microcatheter over thedeployed device, at the site ofdeployment, until it is fully containedwithin the inner lumen of themicrocatheter without damage to thedevice. | Pass |
| Delivery andResheathingForces | The maximum delivery and resheathingforces measured during simulated useclinical conditions. | Pass |
| Re-Sheathing | It shall be possible to re-sheath thedevice, as described in the instructionsfor use, after it has been prepareddeployed and retracted as described inthe instructions for use. | Pass |
| Marker Coil TensileStrength | The minimum tensile strength of theunion between the distal marker coilsand the stent retriever shall meet theacceptance criteria. | Pass |
| System Tensile Strength | The minimum tensile strength of thethrombectomy system is evaluatedto the acceptance criteria. | Pass |
| Torque Strength | The system must not break after 3 fullrotations of the insertion wire. | Pass |
| Ancillary DeviceCompatibility | It shall be possible to safely and reliablyprepare, deploy and retract the device ina nominal and worst-case 3D model perthe instructions for use without damageto any ancillary devices listed. | Pass |
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Performance Testing - Animal
A Good Laboratory Practice (GLP) safety study of the pRESET® Thrombectomy Device in a swine model was executed. This study was initiated to assess the safety and performance of the pRESET device in comparison to a control by evaluating worst-case device use (e.g., 3 passes and 6 resheathings of the retrieval device), clot removal, recanalization and device usability performance at both sub-acute (Day 3) and chronic endpoints (Day 30). The control device used for the purpose of the study was the Solitaire™ 2 Revascularization Device. The safety and performance of the pRESET Thrombectomy Device in a swine model of acute vascular occlusion was comparable to the control device.
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CLINICAL EXPERIENCE
The pRESET® Thrombectomy Device was the subject of a prospective, multicenter, randomized controlled clinical trial (RCT) to demonstrate the safety and effectiveness of the device, and to evaluate these outcomes against the Solitaire™ Revascularization Device. A summary of the trial design is provided in Table 1.
| Title | pRESET for Occlusive Stroke Treatment (PROST) |
|---|---|
| Trial Phase | Pre-market clearance (IDE G190099) |
| Trial Design | Prospective, multicenter randomized clinical trial |
| Inclusion Criteria | Age $\ge$ 18 years. Clinical signs consistent with acute ischemic stroke. Able to be treated within 8 hours of stroke symptom onset & within 1.5 hours (90 min) from screening CT / MRI to groin puncture. Pre-stroke mRS $\le$ 1. NIHSS $\ge$ 6 at the time of enrollment. If t-PA is indicated, initiation of IV t-PA should be administered as soon as possible and no later than 3 hours of onset of stroke symptoms, with investigator verification that the subject has received/is receiving the correct IV t-PA dose (0.9 mg/kg) for the estimated weight. eTICI $\le$ 1 confirmed by angiography that is accessible to the mechanical thrombectomy device in the following locations: Intracranial internal carotid M1 and/or M2 segment of the MCA Carotid terminus Vertebral artery Basilar artery NOTE: M1 segment of the MCA is defined as the arterial trunk from its origin at the ICA to the first bifurcation or trifurcation into major branches neglecting the small temporal-polar branch. ASPECTS score must be 6-10 on NCCT or DWI-MRI. If automated core volume assessment software is used: MR diffusion-weighted imaging (DWI) $\le$ 50 cc Computed tomography perfusion (CTP) core $\le$ 50 cc Subject is willing to conduct protocol-required follow-up visits. A valid signed and dated informed consent by participant or LAR (legally authorized representative) has been obtained. |
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| Exclusion Criteria | • Received IA t-PA prior to enrollment in the study.• Female who is pregnant or lactating or has a positive pregnancy test at time of admission.• Rapid neurological improvement prior to study enrollment suggesting resolution of signs/symptoms of stroke.• Known serious sensitivity to radiographic contrast agents.• Known sensitivity to nickel, titanium metals, or their alloys.• Enrolled in other investigational studies that would interfere with study endpoints.• Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency.• Known renal failure as defined by a serum creatinine > 2.0 mg/dl (or 176.8 µmol/l) or glomerular filtration rate (GFR) < 30.• Requires hemodialysis or peritoneal dialysis, or has a contraindication to an angiogram.• Life expectancy of less than 90 days.• Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT or MRI scan is normal.• Suspicion of aortic dissection.• Comorbid disease or condition that would confound the neurological and functional evaluations or compromise survival or ability to complete follow-up assessments.• Known to currently use or has a recent history of illicit drug(s) or abuses alcohol (defined as regular or daily consumption of more than four alcoholic drinks per day).• Known arterial condition (e.g., proximal vessel stenosis or pre-existing stent) that would prevent the device from reaching the target vessel and/or preclude safe recovery of the device.• Requires balloon angioplasty or stenting of the carotid artery at the time of the index procedure.• Angiographic evidence of carotid dissection. |
|---|---|
| IMAGING: | • CT or MRI evidence of hemorrhage on presentation.• CT or MRI evidence of mass effect or intra-cranial tumor (except small meningioma).• CT or MRI evidence of cerebral vasculitis.• CT or MRI-DWI showing ASPECTS 0-5. Alternatively, if automated core volume assessment software is used, MRI-DWI or CTP core > 50 cc.• CT or MRI shows evidence of carotid dissection or complete cervical carotid occlusion requiring a stent.• Any imaging evidence that suggests, in the opinion of the investigator, the subject is not appropriate for mechanical thrombectomy intervention (e.g., inability to navigate to target lesion, moderate/large infarct with poor collateral circulation, etc.).• Occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior/posterior circulation) as confirmed by angiography, or clinical evidence of bilateral strokes or strokes in multiple territories. |
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| Randomization | 1:1 using stratification factors:• Age: ≥ 65 and < 65• Site of occlusion: ICA, MCA and BA• Baseline/Enrollment NIHSS score: < 17 and ≥ 17• Prior IV t-PA usage: Yes and No• Time to symptom onset: ≥ 4 hours and < 4 hours |
|---|---|
| Sample Size | • Intent-to-Treat Population: 340 subjects: 173 pRESET & 167 Solitaire• Per Protocol Population: 266 subjects: 138 pRESET & 128 Solitaire• As Treated Population: 322 subjects: 166 pRESET & 156 Solitaire |
| Follow-Up | 24 hours, 7 Days, 30 Days & 90 Days |
| Primary Endpoints | • Proportion of subjects with mRS ≤ 2 at 90 days after the index procedure• Proportion of subjects with device- or procedure-related symptomaticintracerebral hemorrhage (sICH) within 24 hours (-8/+12 hrs) of the indexprocedure |
| Secondary Endpoints | • Proportion of subjects with eTICI 2b50 or greater flow in the target vesselpost-procedure with ≤ 3 passes of the assigned study device• Proportion of subjects with eTICI 2c or greater following the first pass of theassigned study device• Overall mortality at 90 days following the index stroke• Distribution of mRS shift at 90 days across the entire spectrum of |
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enox
Traditional 510(k) pRESET® Thrombectomy Device
A total of 340 subjects were enrolled and randomized into PROST at 24 sites across the US (n=19) and Germany (n=5): 173 in the pRESET® arm and 167 in the Solitaire arm. Key subject baseline demographics were similar across the two arms (Table 2).
| Table 2: Key Baseline Demographics | |||
|---|---|---|---|
| Parameter | Enrolled(N=340) | pRESET(N=173) | Solitaire(N=167) |
| Age (years) | |||
| N | 340 | 173 | 167 |
| Median (Min, Max) | 73.0 (29, 96) | 73.0 (29, 96) | 75.0 (31, 96) |
| Gender | |||
| N | 340 | 173 | 167 |
| Male | 170 (50.0%) | 90 (52.0%) | 80 (47.9%) |
| Female | 170 (50.0%) | 83 (48%) | 87 (52.1%) |
| NIHSS at Admission | |||
| N | 339 | 173 | 166 |
| Median (Min, Max) | 16.0 (6, 31) | 16.0 (6, 29) | 16.0 (6, 31) |
| mRS before Stroke | |||
| 0 | 251 (73.8%) | 130 (75.1%) | 121 (72.5%) |
| 1 | 84 (24.7%) | 41 (23.7%) | 43 (25.7%) |
| 2 | 3 (0.9%) | 1 (0.6%) | 2 (1.2%) |
| Not Reported | 2 (0.6%) | 1 (0.6%) | 1 (0.6%) |
| ASPECTS Score | |||
| N | 336 | 171 | 165 |
| Median (Min, Max) | 9.0 (6, 10) | 9.0 (6, 10) | 9.0 (6, 10) |
| Core Infarct Size (cc) | |||
| N | 117 | 60 | 57 |
| Median (Min, Max) | 10.0 (0, 85) | 6.5 (0, 66) | 14.0 (0, 85) |
| Target Occlusion Location | |||
| Left Hemisphere | 146 (42.9%) | 78 (45.1%) | 68 (40.7%) |
| Right Hemisphere | 161 (47.4%) | 81 (46.8%) | 80 (47.9%) |
| Posterior | 17 (5.0%) | 9 (5.2%) | 8 (4.8%) |
| Not Reported | 16 (4.7%) | 5 (2.9%) | 11 (6.6%) |
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The Intent-to-Treat (ITT) population (n=340) included all subjects who had a signed informed consent form (ICF) and were randomized.
The Per Protocol (PP) population (n=266) included all subjects who underwent treatment with a study device, met the eligibility criteria and had primary effectiveness outcome data.
The As Treated (AT) population (n=322) included all subjects who underwent treatment with a study device, irrespective of device assignment. There were 0 treatment crossovers.
| Table 3: Final Subject Disposition | |||
|---|---|---|---|
| Parameter | Enrolled(N=340) | pRESET(N=173) | Solitaire(N=167) |
| Randomized | 340 (100.0%) | 173 (100.0%) | 167 (100.0%) |
| Underwent Study Procedure1 | 322 (94.7%) | 166 (96.0%) | 156 (93.4%) |
| Completed Follow-Up | |||
| 24 hour | 322 (94.7%) | 166 (96.0%) | 156 (93.4%) |
| Day 7 | 296 (87.1%) | 152 (87.9%) | 144 (86.2%) |
| Day 30 | 283 (83.2%) | 144 (83.2%) | 139 (83.2%) |
| Day 902 | 265 (77.9%) | 137 (79.2%) | 128 (76.6%) |
| Discontinued from the Study3 | |||
| Death | 47 (13.8%) | 24 (13.9%) | 23 (13.8%) |
| Withdrawn | 24 (7.1%) | 10 (5.8%) | 14 (8.4%) |
| Lost to Follow-Up | 2 (0.5%) | 0 (0.0%) | 2 (1.2%) |
1 Following randomization, 18 subjects did not undergo study Procedure for the following reasons: clot migrated, resolved, or could not be reached, the subject did not meet all eligibility criteria (including absence of a subarachnoid hemorrhage), the study device was not used, or a wire perforation occurred.
² The total number of subjects who completed Day 90 follow-up (n=265) differs from the total number of subjects in the PP population (n= 266) as these two populations are not composed of the same subjects who died prior to Day 90 are excluded from Completed Follow-Up Day 90 but may be included in the PP population as a primary effectiveness outcome data point is available i.e., mRS = 6. Subjects who attended Day 90 follow-up are included in the Completed Follow-Up Day 90 but may be excluded from the PP population as they had a deviation against the eligibility criteria.
3 Two subjects did not attend the Day 90 follow-up visit; however, these patients remained active in the study at 90 days postprocedure and were confirmed to be alive at Day 90.
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The pRESET® Thrombectomy Device was demonstrated to be non-inferior to the Solitaire™ Revascularization Device in the restoration of blood flow in the neurovasculature (eTICI ≥ 2b50) and for the treatment of acute ischemic stroke to reduce disability in patients (mRS ≤ 2 at 90 days) (Table 4). This can be achieved with a similar safety profile to the Solitaire™ Revascularization Device, with the pRESET® Thrombectomy Device demonstrated to be noninferior in the occurrence of device- or procedure-related symptomatic intracerebral hemorrhage (sICH) within 24 hours of the index procedure (Table 4).
Table 4: Key Outcome Measures (Intent-to-Treat Population)
Primary Effectiveness Endpoint After 90 days following the procedure, is the lower bound of the 1-sided 95% confidence interval of the difference (pRSST minus Solitaire) in global disability (mRS ≤ 2) above the a priori threshold of -12.5%?
| Total Subjects | 90 Day mRS ≤2n (%) | Confidence Interval(Lower Bound, Upper Bound) | |
|---|---|---|---|
| pRESET | 173 | 95 (54.91%) | |
| Solitaire | 167 | 96 (57.49%) | |
| pRESET minus Solitaire | -2.57% | -11.42%, 6.28% |
Primary Safety Endpoint
Within 24 hours (-8/+12 hours) after the study procedure, is the upper bound of the 1-sided 95% confidence interval of the difference (pRESET minus Solitaire) with device-related sICH below the a priori threshold of 5%?
| Total Subjects | 24 Hour sICH n (%) | Confidence Interval(Lower Bound, Upper Bound) | |
|---|---|---|---|
| pRESET | 173 | 0 (0.00%) | . |
| Solitaire | 167 | 2 (1.20%) | . |
| pRESET minus Solitaire | . | -1.20% | -2.58%, 0.19% |
Secondary Effectiveness Endpoint
Following a maximum of 3 passes of the assigned study device, and based on the best eTICI result within ≤ 3 passes, is the lower bound of the 1-sided 95% confidence interval of the difference (pRESET minus Solitaire) in the proportion of patients with eTlCl 2b50 or greater flow in the target vessel post-procedure above the a priori threshold of -12.1%?
| Total Subjects | eTICI ≥ 2b50 n (%) | Confidence Interval(Lower Bound, Upper Bound) | |
|---|---|---|---|
| pRESET | 173 | 146 (84.39%) | . |
| Solitaire | 167 | 149 (89.22%) | . |
| pRESET minus Solitaire | . | -4.83% | -10.84%, 1.19% |
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When any additional device usage or more than three passes of the study device are considered failures, regardless of whether the study device alone achieved eTICI ≥ 2b50 before additional passes were attempted or needed the use of an additional device, the performance of the pRESET® Thrombectomy Device and the Solitaire™ Revascularization Device are listed below for all study populations (Table 5).
| Table 5: Key Outcome Measures with Additional Device Use and > 3 Passes as Failures | |||
|---|---|---|---|
| Parameter | ITT PopulationSuccess n/N (%) | PP PopulationSuccess n/N (%) | AT PopulationSuccess n/N (%) |
| 90 Day mRS ≤2 | |||
| pRESET | 74/173 (42.77%) | 67/138 (48.55%) | 71/166 (42.77%) |
| Solitaire | 68/167 (40.72%) | 60/128 (46.88%) | 68/156 (43.59%) |
| pRESET minus Solitaire | 2.06% | 1.68% | -0.82% |
| Confidence Interval (Lower, Upper Bound) | -6.74%, 10.85% | -8.40%, 11.76% | -9.90, 8.27% |
| eTICI ≥ 2b50 | |||
| pRESET | 124/173 (71.68%) | 105/138 (76.09%) | 121/166 (72.89%) |
| Solitaire | 128/167 (76.65%) | 98/128 (76.56%) | 118/156 (75.64%) |
| pRESET minus Solitaire | -4.97% | -0.48% | -2.75% |
| Confidence Interval (Lower, Upper Bound) | -12.76%, 2.82% | -9.05%, 8.10% | -10.76, 5.26% |
In total, 231 (67.9%) subjects had at least one adverse event with 105 (30.9%) subjects having a serious adverse event.
There was no difference in the number of adverse events (p-value: 0.7340) or serious adverse events (p-value: 0.7117) between the two arms.
The number of subjects who had a device- or procedure-related serious adverse event also did not differ across the arms (p-value: 0.7663).
| Parameter | ITT Population(N=340) | pRESET(N=173) | Solitaire(N=167) | P-Value[1] |
|---|---|---|---|---|
| Adverse Event (AE) | ||||
| Number Subjects (%) | 231 (67.9%) | 119 (68.8%) | 112 (67.1%) | . |
| 95% Exact Confidence Interval | . | (61.3%, 75.6%) | (59.4%, 74.1%) | 0.7340 |
| Serious Adverse Event (SAE) | ||||
| Number Subjects (%) | 105 (30.9%) | 55 (31.8%) | 50 (29.9%) | . |
| 95% Exact Confidence Interval | . | (24.9%, 39.3%) | (23.1%, 37.5%) | 0.7117 |
| Procedure and/or Device Related SAE | ||||
| Number Subjects (%) | 28 (8.2%) | 15 (8.7%) | 13 (7.8%) | . |
| 95% Exact Confidence Interval | . | (4.9%, 13.9%) | (4.2%, 12.9%) | 0.7663 |
1P-Value obtained from a generalized linear model with the randomized treatment as the dependent variable
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phenox
Traditional 510(k) pRESET® Thrombectomy Device
The majority of device- or procedure-related serious adverse events were classed as Nervous System Disorders (Table 7).
| Table 7: Device- or Procedure-Related Serious Adverse Events | |||
|---|---|---|---|
| System Organ ClassPreferred Term | ITT Population(N=340) | pRESET(N=173) | Solitaire(N=167) |
| Cardiac Disorders | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Acute Myocardial Infarction | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Gastrointestinal Disorders | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Vomiting | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Infections & Infestations | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Pneumonia | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Injury, Poisoning & Procedural Complications | 5 (1.5%) | 4 (2.3%) | 1 (0.6%) |
| Post Procedural Stroke | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Vascular Access Site Complication | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Vascular Pseudoaneurysm | 2 (0.6%) | 1 (0.6%) | 1 (0.6%) |
| Vasoplegia Syndrome | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Nervous System Disorders | 21 (6.2%) | 9 (5.2%) | 12 (7.2%) |
| Basal Ganglia Hematoma | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Brain Edema | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Cerebral Artery Embolism | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Cerebral Artery Occlusion | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Cerebral Hemorrhage | 2 (0.6%) | 1 (0.6%) | 1 (0.6%) |
| Cerebral Infarction | 2 (0.6%) | 0 (0.0%) | 2 (1.2%) |
| Cerebral Reperfusion Injury | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Cerebrovascular Accident | 3 (0.9%) | 2 (1.2%) | 1 (0.6%) |
| Hemorrhage Intracranial | 3 (0.9%) | 1 (0.6%) | 2 (1.2%) |
| Hemorrhagic Transformation Stroke | 2 (0.6%) | 1 (0.6%) | 1 (0.6%) |
| Hydrocephalus | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Intracranial Mass | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Stroke In Evolution | 2 (0.6%) | 1 (0.6%) | 1 (0.6%) |
| Subarachnoid Hemorrhage | 3 (0.9%) | 1 (0.6%) | 2 (1.2%) |
| Vertebral Artery Dissection | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
| Respiratory, Thoracic & Mediastinal Disorders | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Respiratory Failure | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Vascular Disorders | 2 (0.6%) | 1 (0.6%) | 1 (0.6%) |
| Peripheral Ischemia | 1 (0.3%) | 0 (0.0%) | 1 (0.6%) |
| Vascular Dissection | 1 (0.3%) | 1 (0.6%) | 0 (0.0%) |
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VIII. CONCLUSIONS
phenox Ltd. have demonstrated that the pRESET® Thrombectomy Device is substantially equivalent to the Solitaire™ 2 Revascularization Device (K162539) through a multicenter, prospectively designed, randomized controlled trial. The randomized trial design minimizes the uncertainty and bias of the trial results by allowing the discrimination of patient outcomes that are caused by the pRESET Thrombectomy Device from outcomes that may be caused by other factors. pRESET® Thrombectomy Device has the same intended use, similar technological characteristics, similar materials and the same operating principle as the predicate device. Substantial equivalence is demonstrated through bench, animal and clinical testing.
§ 882.5600 Neurovascular mechanical thrombectomy device for acute ischemic stroke treatment.
(a)
Identification. A neurovascular mechanical thrombectomy device for acute ischemic stroke treatment is a prescription device used in the treatment of acute ischemic stroke to improve clinical outcomes. The device is delivered into the neurovasculature with an endovascular approach, mechanically removes thrombus from the body, and restores blood flow in the neurovasculature.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The patient contacting components of the device must be demonstrated to be biocompatible.
(2) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use, including:
(i) Mechanical testing to demonstrate the device can withstand anticipated tensile, torsional, and compressive forces.
(ii) Mechanical testing to evaluate the radial forces exerted by the device.
(iii) Non-clinical testing to verify the dimensions of the device.
(iv) Non-clinical testing must demonstrate the device can be delivered to the target location in the neurovasculature and retrieve simulated thrombus under simulated use conditions.
(v) Non-clinical testing must demonstrate the device is radiopaque and can be visualized.
(vi) Non-clinical testing must evaluate the coating integrity and particulates under simulated use conditions.
(vii) Animal testing must evaluate the safety of the device, including damage to the vessels or tissue under anticipated use conditions.
(3) Performance data must support the sterility and pyrogenicity of the patient contacting components of the device.
(4) Performance data must support the shelf-life of the device by demonstrating continued sterility, package integrity, and device functionality over the specified shelf-life.
(5) Clinical performance testing of the device must demonstrate the device performs as intended for use in the treatment of acute ischemic stroke and must capture any adverse events associated with the device and procedure.
(6) The labeling must include:
(i) Information on the specific patient population for which the device is intended for use in the treatment of acute ischemic stroke, including but not limited to, specifying time from symptom onset, vessels or location of the neurovasculature that can be accessed for treatment, and limitations on core infarct size.
(ii) Detailed instructions on proper device preparation and use for thrombus retrieval from the neurovasculature.
(iii) A summary of the clinical testing results, including a detailed summary of the device- and procedure-related complications and adverse events.
(iv) A shelf life.