(185 days)
Penumbra Reperfusion Catheters and Separators As part of the Penumbra System, the Reperfusion Catheters and Separators are indicated for use in the revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease (within the internal carotid, middle cerebral - M1 and M2 segments, basilar, and vertebral arteries) within 8 hours of symptom onset. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment.
Penumbra 3D Revascularization Device As part of the Penumbra System, the Penumbra 3D Revascularization Device is indicated for use in the revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease (within the internal carotid, middle cerebral - M1 and M2 segments) within 8 hours of symptom onset. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment.
Penumbra Aspiration Tubing As part of the Penumbra System, the Penumbra Sterile Aspiration Tubing is indicated to connect the Penumbra Reperfusion Catheters to the Penumbra Aspiration Pump.
Penumbra Aspiration Pump The Penumbra Aspiration Pump is indicated as a vacuum source for Penumbra Aspiration Systems.
The Penumbra 3D Revascularization Device is an additional component to the currently available Penumbra System. The Penumbra System's fundamental mechanism of action is aspiration. Aspiration draws clot into the Penumbra Reperfusion Catheter to remove the clot. The 3D Revascularization Device is designed to assist the Reperfusion Catheter with thrombus removal if needed. The device is provided sterile, non-pyrogenic, and intended for single use only.
The provided text describes the 510(k) summary for the Penumbra 3D Revascularization Device, including a clinical study to assess its safety and effectiveness.
Here’s a breakdown of the acceptance criteria and study information:
1. Table of Acceptance Criteria and Reported Device Performance
The main acceptance criteria for this medical device is demonstrated through a non-inferiority clinical study. The primary effectiveness endpoint was reaching a modified Thrombolysis In Cerebral Infarction (mTICI) score of 2-3.
| Acceptance Criteria (Effectiveness) | Reported Device Performance (3D/Penumbra System vs. Penumbra System alone) |
|---|---|
| Non-inferiority to Penumbra System alone for mTICI score of 2-3, with the lower bound of the 90% confidence interval for the difference above -15%. | Difference: 1.0% |
| 90% CI for Difference: (-8.4%, 10.3%) | |
| The lower bound of -8.4% is above -15%, demonstrating non-inferiority. |
| Acceptance Criteria (Safety) | Reported Device Performance (3D/Penumbra System vs. Penumbra System alone) |
|---|---|
| Incidence of device and procedure-related serious adverse events (SAE) within 24 hours post-procedure is acceptable/comparable to predicate. | Procedure Related SAE (24h): 10.2% (3D/Penumbra System) vs. 15.1% (Penumbra System) |
| Device Related SAE (24h): 4.5% (3D/Penumbra System) vs. 5.4% (Penumbra System) |
2. Sample Size Used for the Test Set and Data Provenance
For the clinical study (Penumbra 3D Trial):
- Test Set (Primary Effectiveness Cohort):
- All Patients: N=150
- 3D / Penumbra System arm: N=74
- Penumbra System alone arm: N=76
- Data Provenance: The study was a prospective, randomized, concurrent controlled, multi-center study. The text does not explicitly state the country of origin but typically such trials for FDA approval involve sites within the US or internationally recognized centers.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
- Ground Truth for Effectiveness (mTICI score): Angiographic results were adjudicated by an independent Core Laboratory. The number and specific qualifications of the experts within this laboratory are not detailed in the provided text.
- Ground Truth for Safety (SAEs): Serious adverse events (SAEs) were adjudicated by a Clinical Events Committee. The number and specific qualifications of the experts within this committee are not detailed.
4. Adjudication Method for the Test Set
- Effectiveness (mTICI score): "Angiographic results were adjudicated by an independent Core Laboratory." The specific method (e.g., 2+1, 3+1) is not explicitly stated, but the use of a "Core Laboratory" implies a standardized and expert review process.
- Safety (SAEs): "The primary safety endpoint was adjudicated by a Clinical Events Committee." Similar to effectiveness, the specific method is not detailed, but external committee adjudication suggests a robust review.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, a "multi-reader multi-case (MRMC) comparative effectiveness study" involving human readers improving with AI vs without AI assistance was not conducted or described. This study directly compared two device interventions (3D/Penumbra System vs. Penumbra System alone) and evaluated their impact on patient outcomes. The device itself is not an AI-assisted diagnostic tool for human readers.
6. Standalone (Algorithm Only Without Human-in-the-Loop) Performance
- This question is not applicable as the device is a medical instrument (revascularization device) used directly in a procedure, not an algorithm, and by its nature requires human intervention to be operated. It does not have a standalone "algorithm-only" performance as an AI system would.
7. Type of Ground Truth Used
- Effectiveness: The primary effectiveness ground truth was the modified Thrombolysis In Cerebral Infarction (mTICI) score, which is an angiographic assessment of reperfusion, indicating the level of blood flow restoration in the occluded vessel. This was determined by an independent Core Laboratory.
- Safety: The ground truth for safety involved the reporting and adjudication of Serious Adverse Events (SAEs) by a Clinical Events Committee.
- Secondary Endpoints: Functional outcome at 90 days was assessed using the modified Rankin Scale (mRS) score, which is a measure of neurological disability or dependence in daily activities.
8. Sample Size for the Training Set
- The document describes a clinical trial (Penumbra 3D Trial) that enrolled patients for a comparative effectiveness study. This is an evaluation study, not a study that involves a "training set" in the context of machine learning. Therefore, a training set sample size is not applicable here. The device was likely developed and refined through engineering studies, bench testing, and animal studies (pre-clinical data) before the human clinical trial.
9. How the Ground Truth for the Training Set Was Established
- As a "training set" in the machine learning sense is not applicable to an evaluation of this physical medical device, this question is not relevant. The device's design and functionality were established through the non-clinical data (biocompatibility, bench-top testing, animal studies) and then validated in the clinical trial.
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Image /page/0/Picture/1 description: The image is a black and white logo for the U.S. Department of Health and Human Services. The logo features a stylized image of three human profiles facing to the right, stacked on top of each other. The profiles are connected and appear to be flowing or merging together. The image is surrounded by text that reads "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" in a circular arrangement.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
April 20, 2017
Penumbra, Inc. Ms. Michaela Mahl Senior Manager of Regulatory Affairs One Penumbra Place Alameda, California 94502
Re: K162901
Trade/Device Name: Penumbra 3D Revascularization Device Regulation Number: 21 CFR 870.1250 Regulation Name: Percutaneous Catheter Regulatory Class: Class II Product Code: NRY Dated: March 20, 2017 Received: March 21, 2017
Dear Ms. Mahl:
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. 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 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 (reporting of medical devicerelated adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. 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
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely.
Carlos L. Pena-S
Carlos L. Peña, PhD, MS Director Division of Neurological and Physical Medicine Devices Office of Device Evaluation Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K162901
Device Name Penumbra 3D Revascularization Device
Indications for Use (Describe)
Penumbra Reperfusion Catheters and Separators
As part of the Penumbra System, the Reperfusion Catheters and Separators are in the revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease (within the internal carotid, middle cerebral - M1 and M2 segments, basilar, and vertebral arteries) within 8 hours of symptom onset. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment.
Penumbra 3D Revascularization Device
As part of the Penumbra System, the Penumbra 3D Revascularization Device is indicated for use in the revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease (within the internal carotid, middle cerebral-Ml and M2 segments) within 8 hours of symptom onset. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment.
Penumbra Aspiration Tubing
As part of the Penumbra System, the Penumbra Sterile Aspiration Tubing is indicated to connect the Penumbra Reperfusion Catheters to the Penumbra Aspiration Pump.
Penumbra Aspiration Pump The Penumbra Aspiration Pump is indicated as a vacuum source for Penumbra Aspiration Systems.
Type of Use (Select one or both, as applicable)
| Prescription Use (Part 21 CFR 801 Subpart D) | ☑ |
|---|---|
| Over-The-Counter Use (21 CFR 801 Subpart C) | ☐ |
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510(k) Summary
(as required by 21 CFR 807.92)
Pursuant to Section 12, Part (a)(i)(3A) of the Safe Medical Devices Act of 1990, Penumbra Inc. is providing the summary of Substantial Equivalence for the Penumbra System 3D Revascularization Device.
Sponsor/Applicant Name and Address 1
Penumbra, Inc. One Penumbra Place Alameda, CA 94502 USA
ನ Sponsor Contact Information
Michaela Mahl Senior Manager, Regulatory Affairs Phone: (510) 748-3288 FAX: (510) 217-6414 Email: mmahl@penumbrainc.com
3 Date of Preparation of 510(k) Summary
April 19, 2017
4 Device Trade or Proprietary Name
Penumbra 3D Revascularization Device
Device Classification 5
| Regulatory Class: | II Classification Panel: |
|---|---|
| Neurology | |
| Classification Name: | Percutaneous Catheter |
| Regulation Number: | 21 CFR §870.1250 |
| Product Code: | NRY (Catheter, Thrombus Removal) |
Predicate and Reference Devices 6
| 510(k) Number/Clearance Date | Name of Predicate Device | Name of Manufacturer |
|---|---|---|
| Predicate Device | ||
| K160449 [25May2016] | Penumbra System and Penumbra Pump MAX | Penumbra, Inc. |
| Reference Devices | ||
| K153071 [23Dec2015] | Solitaire™ Platinum RevascularizationDevice | Micro Therapeutics, Inc. d/b/aev3 Neurovascular |
| K161640 [12Jul2016] | Penumbra System ACE 68 ReperfusionCatheter | Penumbra, Inc. |
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7 Predicate Comparison
| Predicate Device | Primary Reference Device | Subject Device | |
|---|---|---|---|
| Predicate 510(k) | Penumbra System : K160449 | Solitaire™ PlatinumRevascularization Device:K153071 | Penumbra 3D Revascularization Device:K162901 |
| Classification | Class II, NRY | Same | Same |
| Indication for Use | Penumbra Reperfusion Catheters andSeparatorsAs part of the Penumbra System, theReperfusion Catheters and Separators areindicated for use in the revascularization ofpatients with acute ischemic strokesecondary to intracranial large vesselocclusive disease (within the internal carotid,middle cerebral – M1 and M2 segments,basilar, and vertebral arteries) within 8 hoursof symptom onset.Penumbra Aspiration TubingAs part of the Penumbra System, thePenumbra Sterile Aspiration Tubing isindicated to connect the PenumbraReperfusion Catheters to the PenumbraPump MAX.Penumbra Pump MAXThe Penumbra Pump MAX is indicated as avacuum source for Penumbra AspirationSystems. | The Solitaire™ PlatinumRevascularization Device isintended to restore blood flow byremoving thrombus from a largeintracranial vessel in patientsexperiencing ischemicstroke within 8 hours of symptomonset. Patients who are ineligiblefor intravenous tissueplasminogen activator (IV t-PA)or who fail IV t-PA therapy arecandidates for treatment. | Penumbra Reperfusion Catheters andSeparatorsAs part of the Penumbra System, theReperfusion Catheters and Separators areindicated for use in the revascularization ofpatients with acute ischemic strokesecondary to intracranial large vesselocclusive disease (within the internalcarotid, middle cerebral - M1 and M2segments, basilar, and vertebral arteries)within 8 hours of symptom onset. Patientswho are ineligible for intravenous tissueplasminogen activator (IV t-PA) or who failIV t-PA therapy are candidates fortreatment.Penumbra 3D Revascularization Device Aspart of the Penumbra System, thePenumbra 3D Revascularization Device isindicated for use in the revascularization ofpatients with acute ischemic strokesecondary to intracranial large vesselocclusive disease (within the internalcarotid, middle cerebral – M1 and M2segments) within 8 hours of symptom onset.Patients who are ineligible for intravenoustissue plasminogen activator (IV t-PA) orwho fail IV t-PA therapy are candidates for treatment. |
| Predicate Device | Primary Reference Device | Subject Device | |
| Predicate 510(k) | Penumbra System : K160449 | Solitaire™ PlatinumRevascularization Device:K153071 | Penumbra 3D Revascularization Device:K162901 |
| treatment.Penumbra Aspiration TubingAs part of the Penumbra System, thePenumbra Sterile Aspiration Tubing isindicated to connect the PenumbraReperfusion Catheters to the PenumbraAspiration Pump.Penumbra Aspiration PumpThe Penumbra Aspiration Pump is indicatedas a vacuum source for PenumbraAspiration Systems. | |||
| System | Aspiration Pump | N/A | SAME as Predicate |
| Components | Aspiration Tubing | N/A | SAME as Predicate |
| Reperfusion Catheter | Micro Catheter | SAME as Predicate | |
| Materials | Separators | Solitaire™ Platinum | 3D Revascularization Device |
| Push-wire | N/A | N/A | N/A |
| Core wire | 304 Stainless Steelor | N/A | SAME as Predicate |
| Nitinol | SAME | N/A | |
| Outer coil | 304 Stainless Steel | N/A | SAME as Predicate |
| Solder joint | Silver Solder (95% Sn / 5% Ag)Gold Solder (80% Au / 20% Sn) | N/A | SAME as Predicate |
| Coating | PTFE Green (PC 8-403G) | N/A | SAME as Predicate |
| Shrink tubing | N/A | PTFE | N/A |
| Predicate Device | Primary Reference Device | Subject Device | |
| Predicate 510(k) | Penumbra System : K160449 | Solitaire™ PlatinumRevascularization Device:K153071 | Penumbra 3D Revascularization Device:K162901 |
| Distal Tip | |||
| Outer coil | 304 Stainless Steel | N/A | SAME as Predicate |
| Inner coil /Marker coils | Platinum Alloy (92% Pt / 8% W) | 90% Platinum / 10% Iridium | SAME as Predicate |
| Attachment tip | N/A | Unknown | 304 Stainless Steel |
| Solder joint | Gold Solder (80% Au / 20% Sn)Silver Solder (95% Sn / 5% Ag) | N/A | Gold Solder (80% Au / 20% Sn)Silver Solder (96.5% Sn / 3.5% Ag) |
| Stent | N/A | Nitinol | Same as Primary Reference |
| RadiopaqueMarkers | N/A | 4 - 5 | Same as Primary Reference |
| Separator tip | Pebax 40D: green (026) ,yellow (032), blue(041), purple (054) | N/A | N/A |
| ID band | Polyolefin (PET) | N/A | N/A |
| Introducer sheath | Pebax / Nylon | PTFE/Grilamid | FEP |
| Dimensions | |||
| - Distal OD [Cone] | 0.022" - 0.045" [0.56mm - 1.14mm] | N/A | N/A |
| - Device OD | N/A | 4mm & 6mm | 4.5 mm |
| - Device UsableLength | N/A | 20mm & 40mm | 20 mm |
| - Push Wire Length | 175 cm - 200 cm | 180 cm | 200 cm |
| Sterilization | EO | SAME | SAME |
| Shelf-Life | 36-Months | 24-Months | 36-Months |
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8 Device Description
The Penumbra 3D Revascularization Device is an additional component to the currently available Penumbra System. The Penumbra System's fundamental mechanism of action is aspiration. Aspiration draws clot into the Penumbra Reperfusion Catheter to remove the clot. The 3D Revascularization Device is designed to assist the Reperfusion Catheter with thrombus removal if needed. The device is provided sterile, non-pyrogenic, and intended for single use only.
9 Indications for Use
Penumbra Reperfusion Catheters and Separators
As part of the Penumbra System. the Reperfusion Catheters and Separators are indicated for use in the revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease (within the internal carotid, middle cerebral - M1 and M2 segments, basilar, and vertebral arteries) within 8 hours of symptom onset. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment.
Penumbra 3D Revascularization Device
As part of the Penumbra System, the Penumbra 3D Revascularization Device is indicated for use in the revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease (within the internal carotid, middle cerebral - M1 and M2 segments) within 8 hours of symptom onset. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment.
Penumbra Aspiration Tubing
As part of the Penumbra System, the Penumbra Sterile Aspiration Tubing is indicated to connect the Penumbra Reperfusion Catheters to the Penumbra Aspiration Pump.
Penumbra Aspiration Pump
The Penumbra Aspiration Pump is indicated as a vacuum source for Penumbra Aspiration Systems.
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10 Summary of Non-Clinical Data
As required under Section 12, Part (a)(i)(3A) of the Safe Medical Devices Act of 1990, a summary of any information regarding substantial equivalence of the device follows.
Included in this section are descriptions of the testing, which substantiates the safe and effective performance of the Penumbra 3D Revascularization Device as well as its substantial equivalence to the predicate devices:
- Biocompatibility .
- . Design Verification (Bench-Top Testing)
- . Design Validation (GLP Animal Testing)
The subject Penumbra 3D Revascularization Device met all established requirements.
10.1 Biocompatibility Testing
Evidence of the biocompatibility of the Penumbra 3D Revascularization Device is derived from the testing used to support the current FDA cleared Penumbra System Separators and a series of studies listed and summarized in the table below.
Biocompatibility tests conducted on the materials of the Penumbra 3D Revascularization Device were selected in accordance with EN ISO 10993 -1 guidelines (Biological Evaluation of Medical Devices) for limited duration (<24 hours), external communicating devices, contacting circulating blood. All studies were conducted pursuant to 21 CFR, Part 58, Good Laboratory Practices. In summary, nonclinical testing found the Penumbra 3D Revascularization Device to be biocompatible according to the requirements of EN ISO 10993 requirements.
| Test | Method | Results |
|---|---|---|
| In VitroCytotoxicity | ISO Elution Test(MEM Extract) | No evidence of cell lysis ortoxicity |
| Sensitization | ISO Maximization Testfor DelayedHypersenitivity | Non-Sensitizing |
| AcuteIntracutaneousReactivity(Irritation) | ISO Intracutaneous(Intradermal) InjectionTest | No evidence of irritation |
| Acute SystemicToxicity | ISO Acute SystemicInjection Test | No evidence of systemictoxicity |
| Rabbit PyrogenStudy | USP Material-MediatedRabbit Pyrogen Test | No evidence of material-mediated pyrogenicity |
| Hemo-compatibility |
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| Test | Method | Results |
|---|---|---|
| - In Vitro Hemolysis | ASTM Methode(Extraction & DirectContact) | Non-Hemolytic |
| - In VitroCoagulation (PT,PTT) | Prothrombin Time (PT)Assay | Coagulation times are notsignificant different thancorresponding control |
| Partial ThromboplastinTime (PTT) Assay | Non-Thrombogenic | |
| ComplementActivation | C3a and SC5b-9through Enzyme Assay | No greater biologicalresponse thancorresponding control |
| DogThrombogenicity | Thrombogenicity Studyin Dogs - ISO | Non-Thrombogenic |
| Genotoxicity | ||
| - Mouse Lymphoma | Mouse LymphomaMutagenesis Assay -ISO | Non-Mutagenic |
| - AmesMutagenicity | Ames Test | Non-Mutagenic |
| - In Vivo MouseMicronucleus | Micronucleus Assay -ISO | Non-Mutagenic |
In summary non-clinical testing substantiates that the Penumbra 3D Revascularization Device is non-cytotoxic, non-sensitizing, non-irritating, non-toxic, non-pyrogenic, nonhemolytic, and non-thrombogenic.
10.2 Bench-top Testing
The physical and mechanical properties of the Penumbra 3D Revascularization Device was assessed using standard test methods and pre-determined acceptance criteria. The following tests were performed and all tests passed successfully:
| Attribute | Specification | Result |
|---|---|---|
| Pouch Seal Strength | Minimum value per specification | Pass |
| Dimensional / VisualInspection | These evaluations confirm that the units used in thisDesign Verification testing meet all product specifications. | Pass |
| Simulated Use[Intracranial Access,Vessel Access EntryPerformance,Delivery/RetrievalForces & ClotRemoval] | Simulated use testing of the Penumbra 3DRevascularization Device was performed with accessorydevices in an anatomical model which simulated thetortuosity of the neurovasculature. Devices were deliveredthrough the tortuous anatomical model to evaluate theeffectiveness of the devices to remove clots and that theReperfusion Catheter does not collapse under vacuum. | Pass |
| Particulate Testing | $\ge$ 10 μm will be $\le$ 6000 particles | Pass |
| $\ge$ 25 μm will be $\le$ 600 particles | Pass | |
| $\ge$ 75 μm will be measured for informational purposes only(FIFO) | FIFO | |
| $\ge$ 125 μm will be measured for informational purposesonly (FIFO) | FIFO |
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| Attribute | Specification | Result |
|---|---|---|
| Radial Pressure | Value within the specification range | Pass |
| Device Af | Maximum value per specification | Pass |
| Tensile Strength -Markerband | Minimum value per specification | Pass |
| Tensile Strength -Wire Attachment | Minimum value per specification | Pass |
| Corrosion | Specimens will be free from signs of corrosion. | Pass |
| Kink Resistance | No kinking when formed in a defined radius. | Pass |
| Torsion Response | Minimum value per specification | Pass |
The results of the tests appropriately address the physical and mechanical performance expectations of the device. This is further supported by the surgical handling and performance results reported in the in vivo study. Based on these overall results, the physical and mechanical properties of the subject Penumbra 3D Revascularization Device is acceptable for the intended use and substantially equivalent to the predicate device.
10.3 Animal Study
Two animal studies were conducted to evaluate the safe use of the Penumbra 3D Revascularization Device, one study in a rabbit model [Chronic Safety Study] and one study in a swine model [Acute Performance Study]. The studies concluded that:
- No vessel injury was noted on the final angiograms following the vessel response procedure.
- · No abnormal gross or histology findings were noted in test vessel segments.
- · The use of the Penumbra System 3D Revascularization Device resulted in no significant vascular response in these experimental conditions.
11 Clinical Study
The Penumbra 3D Trial was a non-inferiority study that compared the safety and effectiveness of the Penumbra 3D Revascularization Device, used with the Penumbra System aspiration devices, to that of Penumbra System alone for the revascularization of acute ischemic stroke patients with a large vessel occlusion.
Penumbra 3D Trial CLINICAL DATA SUMMARY
The Penumbra 3D Trial was a non-inferiority study that compared the safety and effectiveness of the Penumbra 3D Revascularization Device. used with the Penumbra System aspiration devices, to that of Penumbra System alone for the revascularization of acute ischemic stroke patients with a large vessel occlusion. This was a prospective, randomized, concurrent controlled, non-inferiority design, multi-center study. Patients presenting with symptoms of acute ischemic stroke and evidence of a large vessel occlusion (>2.5mm in diameter) in the cerebral circulation were assigned to either the 3D Revascularization Device with Penumbra
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System arm (3D/Penumbra System) or the Penumbra System alone arm. Each treated patient was assessed for 3 months after randomization.
Statistical Analysis
The objective of the statistical analysis was to assess if the effectiveness of 3D/ Penumbra System was non-inferior to Penumbra System alone as defined by a modified Thrombolysis In Cerebral Infarction scale (mTICI) score of 2-3. The pre-specified primary efficacy analysis was conducted in the per protocol population. The primary effectiveness analysis was the difference between the 3D/ Penumbra System group and the Penumbra System alone group (control). A binomial comparison was used to test the null hypothesis that the difference in proportions was less than or equal to -0.15 (Ho: P3D - Pcontrol ≤ -0.15; i.e., that revascularization in the 3D/ Penumbra System group is worse than for the Penumbra System alone group) vs. the one-sided alternative (Hr: P3D - PControl > -0.15). This was equivalent to evaluating that the lower bound of the 90% confidence interval for the difference was above -15%. The sample size calculations assume that 80% of the standard Penumbra System patients experience success (mTICI of 2 to 3) and 80% of the 3D/Penumbra System patients experience success.
Study Procedures
Acute ischemic stroke patients presenting within 8 hours of onset with NIHSS score ≥8 underwent 1:1 randomization to 3D/ Penumbra System or Penumbra System alone. The primary effectiveness endpoint was mTICI score of 2-3 with a 15% margin for non-inferiority. Device and procedure-related serious adverse events (SAEs) at 24 hours were the primary safety endpoint. Key secondary endpoints were functional independence at 90 days defined by a modified Rankin Scale (mRS) score of 0-2, symptomatic intracranial hemorrhage (sICH) and all cause mortality. All patients were followed for 90 days.
Key Inclusion Criteria
- From 18 to 85 years of age .
- Present with symptoms consistent with an acute ischemic stroke for . revascularization within 8 hours from symptom onset
- . Refractory to or not eligible for IV rtPA therapy, e.g., presenting between 0 and 3 hours from symptom onset AND contraindicated for IV rtPA, or presenting between 3 and 8 hours of symptom onset, or evidence from vascular imaging of persistent occlusion after IV rtPA
- Evidence of a large vessel (>2.5mm in diameter) occlusion in the cerebral . circulation
- NIH Stroke Scale (NIHSS) score >8 .
- Signed informed consent ●
Key Exclusion Criteria
- History of stroke in the past 3 months ●
- Females who are pregnant
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- Pre-existing neurological or psychiatric disease that could confound the study results such as a pre-stroke mRS score >1
- Known severe allergy to contrast media
- Uncontrolled hypertension (defined as systolic blood pressure >185 mmHg ● or diastolic blood pressure >110 mmHg)
- CT evidence of the following conditions at randomization:
- Significant mass effect with midline shift
- Large infarct region >1/3 of the middle cerebral artery territory
- -Evidence of intracranial hemorrhage
- Angiographic evidence of an arterial stenosis proximal to the occlusion that ● could prevent thrombus removal
- Angiographic evidence of preexisting arterial injury
- Rapidly improving neurological status prior to enrollment
- Bilateral stroke
- Intracranial tumors
- Known history of cerebral aneurysm or arteriovenous malformation
- Known hemorrhagic diathesis, coagulation deficiency, or on anticoagulant therapy with an International Normalized Ratio (INR) of >1.7
- Baseline platelets <50,000
- Use of IV heparin in the past 48 hours with PTT >1.5 times the normalized ● ratio
- Baseline glucose <50mg/dL or >300mg/dL
- Life expectancy less than 90 days prior to stroke onset ●
- Participation in another clinical investigation that could confound the ● evaluation of the study device
Summary of reasons for exclusion of enrolled subjects, especially those based on angiographic criteria
Of the 198 patients enrolled, a total of 15 patients were excluded for angiographic reasons. These patients along with 5 patients who did not meet key inclusion/exclusion criteria and 5 patients who did not receive the assigned treatment were excluded from the Per Protocol analysis.
| Randomized (ITT)* | Primary Effectiveness Cohort+ | |||||
|---|---|---|---|---|---|---|
| AllPatients(N=198**) | 3D /PenumbraSystem(N=98) | PenumbraSystem(N=100) | AllPatients(N=150) | 3D /PenumbraSystem(N=74) | PenumbraSystem(N=76) | |
| CompletedStudy | 70.2%(139/198) | 68.4%(67/98) | 72.0%(72/100) | 68.7%(103/150) | 63.5%(47/74) | 73.7%(56/76) |
| Died prior to90 day follow-up | 22.7%(45/198) | 19.4%(19/98) | 26.0%(26/100) | 24.0%(36/150) | 23.0%(17/74) | 25.0%(19/76) |
| Earlytermination | ||||||
| Subject Lostto Follow-Up | 5.1%(10/198) | 8.2% (8/98) | 2.0% (2/100) | 6.0%(9/150) | 10.8%(8/74) | 1.3% (1/76) |
Patient Disposition Summary of Patient Disposition
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| Randomized (ITT)* | Primary Effectiveness Cohort+ | |||||
|---|---|---|---|---|---|---|
| SubjectWithdrawal | 2.0%(4/198) | 4.1% (4/98) | 0%(0/100) | 1.3%(2/150) | 2.7%(2/74) | 0%(0/76) |
- All patients who were consented and randomized were included in the intent to treat (IT) population. The ITT population included all subjects with data for a given endpoint; results were assessed according to randomized assignment regardless of the treatment actually received.
** There were 8 patients not treated with any component of the Penumbra System due to the resolution of thrombus, inability to access target vessel due to tortuous anatomy and angiographic exclusion.
-The primary effectiveness cohort excluded patients that did not meet angiographic criteria (n=15), inclusion or exclusion criteria was not met (n=5), treatment was not as assigned (n=5), patients received tPA > 3 hours (n=14) or patients that had a baseline TICI ≥ 2a (n=9), which resulted in a primary effectiveness cohort of 150 patients.
The large vessel occlusions randomized include the following target vessels.
| Randomized (ITT) | Primary Effectiveness Cohort | |||||
|---|---|---|---|---|---|---|
| TargetVessel | All Patients(N=198) | 3D / PenumbraSystem(N = 98) | PenumbraSystem(N = 100) | AllPatients(N=150) | 3D / PenumbraSystem(N =74) | PenumbraSystem(N =76) |
| ICA | 19.7% ( 39 /198) | 15.3% ( 15 / 98) | 24.0% ( 24 /100) | 19.3%(29/150) | 14.9% (11/74) | 23.7%(18/76) |
| MCA M1 | 63.6% (126/198) | 66.3% ( 65 / 98) | 61.0% ( 61 /100) | 68.7%(103/150) | 71.6%(53/74) | 65.8%(50/76) |
| MCA M2 | 13.6% ( 27 /198) | 15.3% ( 15 / 98) | 12.0% ( 12 /100) | 10.7%(16/150) | 13.5% (10/74) | 7.9% (6/76) |
| PCA | 1.0% ( 2 /198) | 1.0% ( 1 / 98) | 1.0% ( 1 / 100) | 0.7%(1/150) | 0%(0/74) | 1.3% (1/76) |
| Basilar | 1.0% ( 2 /198) | 1.0% ( 1 / 98) | 1.0% ( 1 /100) | 0.7%(1/150) | 0%(0/74) | 1.3% (1/76) |
Patient Target Vessels in Penumbra 3D Trial
Primary Effectiveness Endpoint
The Primary Effectiveness Endpoint was revascularization of the occluded target vessel. Revascularization was defined by a mTICI score of 2 to 3 following use of the 3D/Penumbra System and prior to the use of any additional therapies or adjunctive devices. Use of IA lytic was considered a treatment failure. Patients administered IV rtPA > 3 hours from stroke symptom onset or having an mTICI score of 2a or greater prior to intervention are excluded. Angiographic results were adjudicated by an independent Core Laboratory.
| Primary Effectiveness Endpoint | All Patients | 3D / Penumbra System | Penumbra System | Difference (90 % CI)† |
|---|---|---|---|---|
| mTICI score of 2 to 3, Per Protocol,% (n/N) | 86.0%(129/150) | 86.5 %(64/74) | 85.5%(65/76) | 1.0 %(-8.4%, 10.3%) |
*Wald confidence intervals
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Primary Safety Endpoint
The Primary Safety Endpoint was incidence of device and procedure-related serious adverse events that occurred within 24 hours post-procedure. The primary safety endpoint was adjudicated by a Clinical Events Committee. Each site was permitted two roll-in patients and these patients were the first patients the physicians used the 3D Revascularization Device. The primary safety endpoint data for the roll-in patients is included.
| Roll-In | Randomized (As Treated) | |||
|---|---|---|---|---|
| Primary Safety Endpoint (As Treated) | Roll-In | All Patients | 3D /PenumbraSystem | PenumbraSystem |
| Procedure Related Serious Adverse Event,% (n/N) | 7.9% (6/76) | 12.7% (23/181) | 10.2% (9/88) | 15.1% (14/93) |
| Device Related Serious Adverse Event, %(n/N)SAE during the procedure | 6.6% (5/76) | 5.0% (9/181) | 4.5% (4/88) | 5.4% (5/93) |
Secondary Endpoint
The Secondary Endpoint was functional outcome at 90 days post-procedure. Patients administered IV rtPA > 3 hours from stroke symptom onset (n=14) or having an mTICI score of 2a or greater prior to intervention (n=9) are excluded. Eight (8) patients who were not treated with any component of the Penumbra System are also excluded. Patients who received any additional therapies or adjunctive devices following the use of the Penumbra System (+3D) are imputed as an outcome failure.
Functional Outcome at 90 Days Post-Procedure (modified ITT)
| Outcome (ITT) | All Patients (N=167) | 3D / Penumbra System (n=82) | Penumbra System (n=85) | p-value |
|---|---|---|---|---|
| mRS 0-2 | 37.5% (57/152) | 38.0% (27/71) | 37.0% (30/81) | 1.0 |
Note: P-value from two-sided Fisher's Exact test for categorical assessment between groups.
Each specific SAE through 90 days occurring in more than 2% of patients (As Treated)
| Serious Adverse Event MedDRAPreferred Term | All Patients(N=181) | 3D / PenumbraSystem(N=88) | PenumbraSystem(N=93) |
|---|---|---|---|
| Stroke in evolution | 15.5% (28/181) | 12.5% (11/88) | 18.3% (17/93) |
| Haemorrhagic transformation stroke | 2.8% (5/181) | 2.3% (2/88) | 3.2% (3/93) |
| Haemorrhage intracranial | 2.2% (4/181) | 2.3% (2/88) | 2.2% (2/93) |
| Respiratory failure | 5.0% (9/181) | 2.3% (2/88) | 7.5% (7/93) |
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| Serious Adverse Event MedDRAPreferred Term | All Patients(N=181) | 3D / PenumbraSystem(N=88) | PenumbraSystem(N=93) |
|---|---|---|---|
| Acute respiratory failure | 2.8% ( 5/181) | 4.5% ( 4/88) | 1.1% ( 1/93) |
| Pulmonary embolism | 2.2% ( 4/181) | 2.3% ( 2/88) | 2.2% ( 2/93) |
| Dysphagia | 8.3% (15/181) | 9.1% (8/88) | 7.5% ( 7/93) |
| Atrial fibrillation | 3.3% ( 6/181) | 3.4% ( 3/88) | 3.2% ( 3/93) |
| Deep vein thrombosis | 2.2% ( 4/181) | 1.1% ( 1/88) | 3.2% ( 3/93) |
| Renal failure acute | 2.2% ( 4/181) | 4.5% ( 4/88) | 0.0% ( 0/93) |
| Anaemia | 2.2% ( 4/181) | 2.3% ( 2/88) | 2.2% ( 2/93) |
Categorization of SAEs through 90 days by Body System (As Treated)
| Serious Adverse Event by Body System | All Patients(N=181) | 3D / PenumbraSystem (N=88) | Penumbra System(N=93) |
|---|---|---|---|
| Number of Patients with at Least one Serious Adverse Event | 48.1% (87/181) | 43.2% (38/88) | 52.7% (49/93) |
| Nervous system disorders | 26.0% (47/181) | 21.6% (19/88) | 30.1% (28/93) |
| Respiratory, thoracic and mediastinal disorders | 11.0% (20/181) | 10.2% (9/88) | 11.8% (11/93) |
| Gastrointestinal disorders | 9.9% (18/181) | 9.1% (8/88) | 10.8% (10/93) |
| Cardiac disorders | 9.4% (17/181) | 11.4% (10/88) | 7.5% (7/93) |
| Vascular disorders | 5.5% (10/181) | 1.1% (1/88) | 9.7% (9 /93) |
| Infections and infestations | 4.4% (8/181) | 2.3% (2/88) | 6.5% (6/93) |
| Renal and urinary disorders | 2.8% (5/181) | 4.5% (4/88) | 1.1% (1/93) |
| Blood and lymphatic system disorders | 2.2% (4/181) | 2.3% (2/88) | 2.2% (2/93) |
| Injury, poisoning and procedural complications | 2.2% (4/181) | 2.3% (2/88) | 2.2% (2/93) |
| Metabolism and nutrition disorders | 1.7% (3/181) | 2.3% (2/88) | 1.1% (1/93) |
| Endocrine disorders | 0.6% (1/181) | 0.0% (0/88) | 1.1% (1/93) |
| General disorders and administration site conditions | 0.6% (1/181) | 1.1% (1/88) | 0.0% (0/93) |
| Immune system disorders | 0.6% (1/181) | 0.0% (0/88) | 1.1% (1/93) |
| Investigations | 0.6% (1/181) | 0.0% (0/88) | 1.1% (1/93) |
12 Summary of Substantial Equivalence
The subject Penumbra 3D Revascularization Device is substantially equivalent to the predicate device with regard to intended use, operating principle, design concept, materials, shelf-life, packaging and sterilization processes.
§ 870.1250 Percutaneous catheter.
(a)
Identification. A percutaneous catheter is a device that is introduced into a vein or artery through the skin using a dilator and a sheath (introducer) or guide wire.(b)
Classification. Class II (performance standards).