The Penumbra Pivotal Stroke Trial
Safety and Effectiveness of a New Generation of Mechanical Devices for Clot Removal in Intracranial Large Vessel Occlusive Disease
Background and Purpose—The purpose of this clinical evaluation was to assess the safety and effectiveness of the Penumbra System in the revascularization of patients presenting with acute ischemic stroke secondary to intracranial large vessel occlusive disease.
Methods—In this prospective, multicenter, single-arm study, 125 patients with neurological deficits as defined by a National Institutes of Health Stroke Scale score ≥8, presented within 8 hours of symptom onset, and an angiographic occlusion (Thrombolysis In Myocardial Infarction [TIMI] Grade 0 or 1) of a treatable large intracranial vessel were enrolled. Patients who presented within 3 hours from symptom onset had to be ineligible or refractory to recombinant tissue plasminogen activator therapy. All patients were followed clinically for 90 days postprocedure.
Results—A total of 125 target vessels in 125 patients were treated by the Penumbra System. Postprocedure, 81.6% of the treated vessels were successfully revascularized to TIMI 2 to 3. There were 18 procedural events reported in 16 patients (12.8%), 3 patients (2.4%) had events that were considered serious. A total of 35 patients (28%) were found to have intracranial hemorrhage on 24-hour CT of which 14 (11.2%) were symptomatic. All cause mortality was 32.8% at 90 days with 25% of the patients achieving a modified Rankin Scale score of ≤2.
Conclusions—These results suggest the Penumbra System allows safe and effective revascularization in patients experiencing ischemic stroke secondary to large vessel occlusive disease who present within 8 hours from symptom onset.
Despite recent advances in medical and mechanical therapies, ischemic stroke remains a debilitating and often intractable disease with few treatment options for effective acute intervention.1 Current treatment options in the United States are limited to thrombolytics such as recombinant tissue plasminogen activator, administered either intravenously or intra-arterially, or mechanical thrombectomy devices such as the MERCI clot retriever (Concentric Medical, Mountain View, Calif).1 However, despite attempts to build public awareness and reduce the time from stroke onset to intervention following the “time is brain” paradigm that every minute delay in treatment can significantly expand infarct volume, annually <5% of the close to 800 000 patients with ischemic stroke in the United States are being treated by these therapies, resulting in a significant unmet need for this devastating disease.1–3
The Penumbra System is a new generation of neuroembolectomy devices specifically designed to remove thrombus that causes acute ischemic stroke in large intracranial vessels. The system provided 2 revascularization options: first with thrombus debulking and aspiration followed by direct thrombus extraction if clots remained. Results from a European safety trial were recently published4 and led to a CE Mark approval in Europe. The Penumbra System was recently launched for commercial use after receiving 510(k) clearance in the United States from the Food and Drug Administration (FDA) indicated for the revascularization of patients with acute ischemic stroke secondary to large vessel occlusive disease within 8 hours of symptom onset. The direct thrombus extraction component of the System was not included in the FDA clearance but has received the CE Mark. The pivotal trial that led to this 510(k) clearance from the FDA was a prospective, single-arm, 125-patient study designed to assess the safety and effectiveness of the System to reduce clot burden in acute ischemic stroke using the MERCI clot retriever (Concentric Medical) as the predicate device and historical control.5–7 The goal was to prove “substantial equivalence” in safety and effectiveness to the MERCI device in opening clotted cerebral blood vessels in stroke.5 A randomized, active controlled trial was not required for this regulatory pathway. Reported herein are the results from this study.
Materials and Methods
The protocol for this study received Institutional Review Board or Ethics Committee approval at the respective clinical centers before enrolling any patients. Images from angiography and CT/MRI scans were adjudicated by an independent core laboratory. Revascularization was assessed by Thrombolysis In Myocardial Infarction (TIMI) flow classification adopted for the cerebral vasculature.8 Primary safety end points and selected other events were adjudicated by a Clinical Events Committee (CEC) composed of specialists in the areas of neuroradiology, neurology, and interventional neuroradiology (Appendix). Data were monitored by trained internal monitors and a qualified contract research organization (MedPass International, Paris, France).
All patients were required to sign informed consent before enrollment and in cases in which this was not possible, a legally authorized representative must have signed on the patient’s behalf. All eligible subjects were evaluated for neurological and functional status, and an angiographic assessment of the suspected vascular occlusion was obtained. Main inclusion criteria were target patients must present within 8 hours of symptom onset with a baseline National Institutes of Health Stroke Scale (NIHSS) score of ≥8 and an angiographically verified occlusion of a large intracranial vessel. Patients who presented within 3 hours must have been either not eligible or refractory to intravenous recombinant tissue plasminogen activator therapy as defined by the persistence of neurological symptoms and the presence of an occlusion in the target vessel despite the lytic therapy. Patients with extensive infarctions greater than one third of the territory of the middle cerebral artery (MCA), severe edema, and intracranial hemorrhage (ICH) were excluded. Pregnant females were also excluded from participation.
Description of the Penumbra System
Illustrations of the Penumbra System reperfusion catheter, separator, and thrombus removal ring are shown in the Figure.
An arterial access procedure was performed using standard percutaneous techniques under systemic anticoagulants and general anesthesia per local institutional standard of care. For subjects without thrombolytic therapy, heparin was administered per institutional standard of care for endovascular therapy. Four-vessel digital subtraction angiography was used to define the angioarchitecture of the occluded vascular segment. An appropriate guide catheter was then brought into position in the occluded target vessel territory to enable access by the Penumbra reperfusion catheter. All components of the Penumbra System are deliverable through a 6-Fr standard guide catheter. A subject was considered enrolled into the study when the reperfusion catheter was deployed from the guide catheter. Once the appropriate position was achieved proximal to the clot, the guidewire was removed from the Penumbra reperfusion catheter and the Penumbra separator was advanced through the Penumbra reperfusion catheter. The Penumbra aspiration pump was then turned on to initiate revascularization. Reduction of the clot burden by aspiration was accomplished by connecting the reperfusion catheter to the Penumbra aspiration pump, which generated a vacuum of −20 inches/Hg. A continuous aspiration-debulking process was facilitated by advancing and withdrawing the separator through the Penumbra reperfusion catheter into the proximal end of the clot. If thrombus remained, a second accessory method of direct mechanical retrieval by the thrombus removal ring was used to augment revascularization. Thrombus extraction using the thrombus removal ring was accomplished by engaging the clot proximally and extracting the clot under flow arrest conditions by inflating a proximal balloon guide catheter. If the Penumbra System was successful in revascularization of the target vessel to TIMI ≥2, no additional interventions were to be performed.
Thrombus Debulking and Aspiration
Using conventional catheterization techniques under fluoroscopic guidance, the reperfusion catheter was advanced over an appropriate neurovascular guidewire and positioned proximal to the thrombus. An appropriately sized Penumbra separator was selected and introduced into the proximal hub and through the reperfusion catheter.
Aspiration was initiated and maintained at −20 inches/Hg vacuum by the aspiration pump, which was connected to the reperfusion catheter by the aspiration tubing (includes an on/off switch to activate the aspiration). Thrombus was aspirated by opening the valve on the aspiration tubing to the on position and advancing/retracting the separator within the reperfusion catheter to assist with aspiration and removal of the thrombus and to clear the lumen of the reperfusion catheter. If necessary to further remove thrombus, additional reperfusion catheters and separators were used at the discretion of the physician based on vessel size and tortuosity. Pre- and posttreatment digital subtraction angiographies were sent to a core laboratory for adjudication.
Direct Thrombus Extraction
If residual thrombus remained after revascularization attempts using the thrombus debulking and aspiration system, the thrombus removal ring was used to directly engage and remove the remaining thrombus. This was accomplished by placing a balloon guide catheter proximally within the territory of the occluded vascular segment, advancing the reperfusion catheter over an appropriate neurovascular guidewire through the balloon guide catheter, and positioning the reperfusion catheter proximal to the primary occlusion site. A pretreatment angiogram was obtained.
An appropriately sized thrombus removal ring was selected based on the vessel diameter and inserted through the rotating hemostatic valve and into the proximal hub of the Penumbra reperfusion catheter. The tip of the thrombus removal ring was advanced until the ring reached the reperfusion catheter tip. The reperfusion catheter with the undeployed ring inside was advanced until the tip was located approximately 15 mm proximal to the thrombus occlusion site.
Once positioned, the ring was deployed from the reperfusion catheter and advanced to engage the thrombus. The radiopaque markers on the ring were used to ensure that the ring was embedded at least 1 cm into the thrombus. The reperfusion catheter was advanced as necessary to support the ring during engagement so that the distal tip of the reperfusion catheter was embedded in the proximal segment of the occlusion. The thrombus was removed under flow arrest after inflating the balloon guide catheter using a syringe with 50% contrast/saline and slowly withdrawing the combined thrombus removal ring and reperfusion catheter to the distal tip of the balloon guide catheter. The duration of flow arrest was less than 1 minute, which was unlikely to affect patient outcome. The thrombus was entirely contained within the balloon guide catheter and completely withdrawn from the patient. A syringe was used to aspirate approximately 10 mL of blood from the balloon guide catheter to remove any residual thrombus that may have remained after withdrawal of the thrombus removal ring and reperfusion catheter.
Unless indicated, administration of anticoagulants and antiplatelets was suspended for 24 hours posttreatment in most patients. Medical management and acute poststroke care after the procedure was consistent with American Stroke Association guidelines.1 If the Penumbra System was unable to revascularize the target vessel to TIMI 2 or 3, no additional interventions were to be performed. If the investigator performed additional treatments after using the Penumbra System at the site of primary occlusion (ie, other mechanical means or intra-arterial thrombolysis), this was documented as a protocol violation. A CT scan was performed within 24 hours after the procedure to detect the presence of ICH. Symptomatic ICH was defined as CT evidence of a bleed that was associated with a 4-point deterioration on the NIHSS score after the procedure. In the event no NIHSS scores were available after the procedure, the ICH was considered symptomatic if the patient died during the 90-day follow-up. Patients were evaluated for neurological and functional status immediately postprocedure, 7 days posttreatment (or on the day of discharge from the hospital, whichever is earlier), 30 days (±10 days), and 90 days (±10 days) posttreatment.
Administration of Neurological Examination and Stroke Scales
The Principal Investigator at each investigative site was responsible for the administration of the neurological examinations and grading of the patients on the stroke and functional scales: NIHSS and the modified Rankin Scale (mRS). In cases in which a designee was needed, the investigator was responsible for ensuring that he or she was trained and had the appropriate qualifications to perform these functions.
Angiographic Data Collection, Interpretation, and Core Laboratory Review
The effectiveness of the Penumbra System was measured by the ability of the system to achieve revascularization of the target vessel beyond the site of primary occlusion. Revascularization was assessed by TIMI flow classification.8 Before treatment with the Penumbra System, all patients were required to have angiographic documentation of TIMI 0 or TIMI 1 flow in the target vessel at the site of primary occlusion. Revascularization was assessed after treatment with the Penumbra System but before the initiation of any additional interventions or any adjunctive therapies. Successful revascularization was defined as angiographic demonstration of TIMI 2 or TIMI 3 flow at the site of primary occlusion. The investigator made an initial assessment of TIMI flow in the target vessel. Preprocedure and postprocedure angiograms were then sent to an unbiased core laboratory to make a final determination on TIMI flow. The adjudicated measurements were used for final data analysis of the angiographic endpoints. The core laboratory was located at the UKSH Campus Kiel Sektion Neuroradiologie Schittenheimstr in Kiel, Germany (Appendix). The independent core laboratory was also used for reading the 24-hour CT scans to determine if there was evidence of ICH. Subsequently are the European Cooperative Acute Stroke Study (ECASS) classifications for ICH used for this study9–11:
Hemorrhage infarction Type 1 (HI-1): small petechiae along the margins of the infarct;
Hemorrhage infarction Type 2 (HI-2): more confluent petechiae within the infarcted area but without a space-occupying effect;
Parenchymal hematoma Type 1 (PH-1): a hematoma in <30% of the infarcted area with some space-occupying effect; and
Parenchymal hematoma Type 2 (PH-2): a hematoma in >30% of the infarcted area with substantial space-occupying effect or as any hemorrhage lesion outside the infracted area.
Data Safety Monitoring Board
An independent Data Safety Monitoring Board was constituted before patient enrollment (Appendix). The Data Safety Monitoring Board reviewed the incoming safety data with its own independent statistician on an ongoing basis with the authority to terminate the trial if the risks of the Penumbra System outweighed the benefits. The Data Safety Monitoring Board was also granted the authority to recommend a modification to the device, a revision of the protocol, or terminate the study at its discretion.
Clinical Events Committee
The CEC was established to review and adjudicate independently the primary safety end point events of all ICH identified by the core laboratory from the review of the 24-hour CT scans, all deaths that occurred within 30 days from the procedure, serious adverse events that occurred during the procedure, and other events that occurred over the course of the trial. The CEC operation was governed by a charter that was approved by the FDA before the first patient was enrolled. It is also important to point out that the adjudication of ICH from CT scans was in conjunction with the core laboratory and further reviewed by the Data Safety Monitoring Board and FDA.
All study data were entered into an electronic data capture system manufactured by a vendor (Data Matrix Inc, Houston, Texas). For optimum security, the system operated with 128-bit encryption over Secure Sockets Layer. This application was designed to be in full compliance with the International Conference on Harmonization and Good Clinical Practices, the FDA’s Code of Federal Regulations 21 CFR Part 11 Electronic Record and Electronic Signatures, the FDA’s “Guidance: Computerized Systems Used in Clinical Trials,” and the Privacy Rule of the Health Insurance Portability and Accountability Act of 1996. Data entries were performed at the investigational sites. Investigators were required to maintain source documents required by the protocol, including laboratory results, patient report forms, supporting medical records, and informed consent forms. The source documents were used during the regular monitoring visits to verify information captured on the electronic case report forms.
A sample size of 125 was selected for this study to generate at least 115 evaluable patients. A patient was considered evaluable if the patient met eligibility requirements for primary end point assessment and was treated with the Penumbra System. Because this was an uncontrolled study, a formal hypothesis test was not planned for the overall response rate for establishing a TIMI grade of 2 or 3. Assuming a response rate of at least 60%, the expected lower bound of the exact 2-sided 95% CI around the success rate is ≥50.5%. Hence, the proposed sample size provided a sufficient level of precision to establish if the Penumbra System would provide an acceptable performance in establishing revascularization. Standard descriptive statistics for categorical end points were the number and percent of patients with each level of the end point. For numeric end points, the standard descriptive statistics included the number of nonmissing observations (n), the mean, the median, the SD, the minimum value, and the maximum value.
From June 19, 2006, to June 5, 2007, a total of 856 patients were screened of which 125 patients were enrolled at 24 centers in Europe and the United States. The number of patients enrolled by center is summarized in the Appendix. Among the enrolled patients, 125 were treated with the device and found eligible for the primary end point assessment. Thus, all 125 patients are considered evaluable patients, identical in number to the intent-to-treat population, and data from only one population were analyzed and reported. The main reasons for patient exclusion at time of screening were low NIHSS scores, time of presentation exceeded 8 hours, age, CT evidence of mass effect, an established large infarction, and ICH. Five patients were lost to follow-up for which 2 patients were followed to discharge and the other 3 to 30 days postprocedure. All 5 patients were successfully revascularized by the Penumbra System. Table 1 summarizes patient baseline characteristics and stroke score, including locations of vascular occlusion and time from symptom onset to presentation and arterial puncture. At baseline, all 125 enrolled patients (100%) had a TIMI score of 0 or 1 (96.0% were TIMI 0 and 4.0% were TIMI 1). Postprocedure, 81.6% of these patients achieved a TIMI score of 2 or 3 (54.4% had a TIMI score of 2 and 27.2% had a TIMI score of 3). There were 19 procedural events reported in 16 patients (12.8%). These were vasospasm (4), reocclusion of the target vessel (3), dissection (3), perforation (3), ICH (2), subarachnoid hemorrhage (1), anemia (1), embolization of a previously uninvolved vessel (1), and stroke in a new territory (1). Among these, events in 3 patients (2.4%) were rated as serious by the CEC. One patient experienced a large ICH from reperfusion injuries after being successfully revascularized by the Penumbra System. She died 8 days after the procedure. Another patient was also successfully revascularized by the Penumbra System but then experienced an ICH from an attempt by the investigator to treat a distal stenosis by balloon angioplasty. The patient died on the day of the procedure. The third patient had a subarachnoid hemorrhage from a perforation caused by a snare and balloon angioplasty. This was from an attempt to treat a distal occlusion that was not accessible to the Penumbra System after the site of primary occlusion was successfully revascularized. However, it did not progress and he was able to complete the trial with an improvement in neurological status from admission (NIHSS 27 to 19).
A total of 35 patients (28%) experienced ICH of which 14 (11.2%) were symptomatic and 21 were asymptomatic (16.8%). Among all ICHs, 4 were subarachnoid hemorrhages and 2 were ECASS-defined parenchymal hematoma Type 2.9–11 Of the 125 patients enrolled, 12 received intra-arterial lytics as adjunctive therapy of which 6 were targeting the site of primary occlusion and the rest aimed at distal branches. The 6 patients with intra-arterial lytics at the site of primary occlusion were considered protocol violations. Among the 35 patients with ICH, 12 had either intravenous (9 patients) or intra-arterial (3 patients) lytic therapy. Of the 15 patients reported to have symptomatic ICH, 6 patients had either intravenous (4 patients) or intra-arterial (2 patients) lytic therapy. Concomitant use of intravenous or intra-arterial lytic does not seem to be a contributing factor to the rate of ICH observed in this study nor does it pose a safety concern when used in conjunction with the Penumbra System. Among the treated patients, 41.6% achieved good clinical outcome at 30 days as defined by a ≥4-point improvement on the NIHSS score at discharge or a 30-day mRS ≤2. Further analysis was conducted using a criterion of a discharge NIHSS score of 0 to 1 or an improvement of ≥10 points (Tables 2 and 3⇓). The 90-day mRS ≤2 and all-cause mortality were 25% and 32.8%, respectively. Although the System was equally effective in reducing the clot burden in the internal carotid artery (ICA) and MCA, the patients with clots in the MCA tended to fare better than the patients with clots in the ICA in clinical outcome (Table 3). Patients who were successfully revascularized by the Penumbra System tended to have better outcomes than those who were not revascularized across all measures of neurological and functional status regardless of the location of the target vessel (Tables 2 and 3⇓).
An analysis of the independent predictors of patient outcome at 90 days revealed baseline NIHSS scores and procedure time were associated with good functional outcome as defined by a mRS ≤2 at 90 days, whereas baseline NIHSS scores >20, ICA occlusion, and history of cerebrovascular accident were associated with mortality (Table 4). Further analysis also showed an NIHSS score of <20 conferred a significantly better functional outcome and lower mortality (Table 5).
The purpose of this present investigation was to assess the safety and effectiveness of the Penumbra System in reducing clot burden in patients presenting with acute ischemic stroke due to large vessel occlusive disease. This System is a new generation of neurothrombectomy devices specifically designed to remove thrombus through aspiration and direct thrombus extraction. The study was designed as part of the submission to the US FDA for 510(k) clearance using the MERCI clot retriever (Concentric Medical) as the predicate device and historical control.5 The results indicate that the Penumbra System was able to revascularize the site of primary occlusion in >80% of patients, which was higher than those reported for the MERCI device and other established or developmental therapies for acute ischemic stroke (Table 6). The high recanalization rate was independent of target vessel locations. Revascularization was successful in 82.6% of patients presenting with occluded target vessels in the ICA and in 83% of patients presenting with occluded target vessels in the MCA (Table 3). Among the patients treated with the device, 12.8% had procedural complications. Of these, events in 3 patients (2.4%) were considered serious. None were associated with malfunction or breakage of the device. Although the CEC adjudicated these complications as related to the procedure but not to the Penumbra device, Penumbra was used for treatments before the listed adverse events, but other devices were also used. This procedural event rate is quite favorable when compared with the published rates for other interventions such as thrombolytic therapy or mechanical retrieval devices for acute stroke.12–21 They are indicative of the ability of the Penumbra System to access cerebral arteries and safely revascularize the site of primary occlusion in most locations of the brain in the anterior and posterior circulations and often in patients with significant tortuosity impeding vascular access.
This favorable safety profile of the Penumbra System extends to the 24-hour ICH rate of 28%, which is in the low range of the historical rates in this stroke cohort with similar demographics and time of presentation from symptom onset11 such as the Second Prolyse in Acute Cerebral Thromboembolism Trial (PROACT II) (35.9%),13 Interventional Management of Stroke (IMS; 48.8%),17 Mechanical Embolus Removal in Cerebral Ischemia (MERCI) Phase II (35.5%),5 and Multi-MERCI (38.7%).6 In addition, the symptomatic ICH rate of 11.2% was comparable to those reported in the PROACT II (10.9%)13 and Multi-MERCI (9.8%).5 Both rates are within the 95% CIs of these prior studies (Table 6). Symptomatic ICH in this study was defined by evidence of bleeding from 24-hour head CT scans and a ≥4-point increase of the NIHSS score. Recent reports have suggested gradient recalled echo MRI may be more sensitive in the detection of hemorrhagic transformation from an acute ischemic stroke not evident on CT.22,23 If confirmed, this could constitute a limitation of this study, although the comparisons to the historical controls are still valid because the PROACT II and MERCI trials also used CT results in reporting incidents of ICH.
Consistent with the rates of procedural complications and ICH, the 90-day mortality rate of 32.8% was comparable to stroke cohorts in published literature who presented between 6 and 8 hours from symptom onset (Table 6). This rate was lower than that reported in the MERCI 2 trial (43.5%),5 about the same as the Multi-MERCI (30.6%),6 but slightly higher than the placebo patients in PROACT II (26%).13 By location of the target vessels, the highest mortality in this stroke cohort was observed in the ICA (57%) followed by the MCA (29%) and the posterior circulation vessels in the vertebrobasilar arteries (21%; Table 2). A review of the literature indicates the expected mortality rates ranged from 27% to 78% for the MCA,13 57% in the ICA,18 and close to 90% in the basilar artery.19,20 Given the small sample size and the lack of a concurrent control group, it is not possible to define the extent to which the Penumbra System affects mortality beyond concluding that its use is not associated with a higher than expected mortality.
Patient neurological recovery and functional outcomes showed improvement with 25% having either a NIHSS score of 0 to 1 or a ≥10-point improvement at discharge and 25% having an mRS score of ≤2 at 90 days. This 90-day mRS score was comparable to the patients in the MERCI 2 trial with 27.7%, but lower than the treated group in the PROACT II study with 40%.5,13 Considering the high revascularization rate of the patients treated with the Penumbra System, the 90-day mRS score is lower than expected. The cause of the disparity between the rate of revascularization and the functional status of these patients at 90 days remains unclear in this single-arm study. It is possible that revascularization by the Penumbra System did not improve the patients’ activities of daily living at 90 days poststroke. This is unlikely because analysis of open versus closed vessels in this study revealed a clear benefit of revascularization across all measures of neurological and functional status, including mortality (Tables 2 and 3⇑). Another possibility is that the disparity may be related to the difference in the baseline NIHSS scores, particularly in light of the results from multivariate analysis that identified the presenting NIHSS scores of >20 were associated with poor outcome (Tables 4 and 5⇑). However, there is no evidence that the mean NIHSS scores or other patient characteristics at baseline were different from these other studies. Because this trial is designed primarily to evaluate the safety and effectiveness of the Penumbra thrombectomy device to acutely reduce clot burden, not functional outcome, it is possible that the low 90-day mRS rate is a spurious finding related to the lack of statistical power from the small sample size for this study. Indeed, our analysis indicated that there is considerable overlap in the 95% CI of these variables across all studies (Table 6). A heterogeneous study population may be a contributing factor because imaging was not used to define the presence of salvageable ischemic penumbra at study entry. Therefore, an absence of imaging-guided patient selection and a historical control design may render elusive a definitive conclusion on long-term outcome. Ultimately, the effect of revascularization on neurological recovery and functional outcome may only be resolved by a concurrent controlled trial using clearly defined tools for imaging-guided patient selection.
In summary, results from this study showed that the Penumbra System allows safe and effective revascularization in patients experiencing ischemic stroke secondary to large vessel occlusive disease who present within 8 hours from symptom onset. The question of whether such revascularization leads to improved neurological recovery and a better functional outcome than medical management alone will require future prospective, concurrently controlled trials in well-selected patients presenting with acute ischemic stroke.
Appendix: The Penumbra Pivotal Stroke Trial Investigators
Clinical Events Committee
David Langer, MD (CEC Chairman) Albert Einstein School of Medicine, New York, NY; Dileep Yavagal, MD, Albany Medical Center, Albany, NY; and Robert Stingele, MD, Universitatsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany.
Data Safety Monitoring Board
Michael Alexander, MD (Data Safety Monitoring Board Chairman), Cedars Sinai Neurovascular Center, Los Angeles, Calif; Vallabh Janardhan, MD, University of Minnesota, Minneapolis, Minn; Prof Marius Hartmann, MD, Universitätsklinikum Heidelberg, Heidelberg, Germany. George DeMuth, PhD (Independent Statistician), Stat-Tech Services, LLC.
Imaging Core Laboratory
Professor Olav Jansen, MD, Universitatsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany.
Study Coordinating Center
Siu Po Sit, PhD (Trial Coordinator), Penumbra Inc; Arani Bose, MD (Medical Monitor), Penumbra Inc.
Participating Centers With Principal Investigator (PI) and Co-Investigator (Co-PI) in Order of Enrollment (N)
Oregon Health Sciences, Providence Portland Medical Center, Portland, Ore (15) PI: Wayne Clark, MD, Co-PI: Helmi Lutsep, MD, Stanley Barnwell, MD, PhD, Gary Nesbit, MD, Robert Egan, MD, Elizabeth North, DO, Lisa Yanase, MD, Ted Lowenkopf, MD, Bryan Petersen, MD. PI for Germany: Iris Quasar Grunwald, MD; Ludwig Maximilians Universitat Munchen, Germany, and Friedrich Schiller Universitaet Jena (15) PI: Thomas Mayer, MD. Universitatsklinikum Erlangen, Germany (11) PI: Arnd Doerfler, MD, Co-PI: Tobias Struffert, MD, Tobias Engelhorn, MD, Gregor Richter, MD. Universitätsklinikum des Saarlandes, Germany (10) PI: Iris Quasar Grunwald, MD. Co-PI: Wolfgang Reith, MD. Klinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany (9) PI: Joachim Berkefeld MD. St Joseph’s Radiology Hospital, St Paul’s United Hospital, St Paul, Minn (9) PI: Michael Madison, MD, Co-PI: Mark Myers, MD, James Goddard, MD, Jeffrey Lassig, MD. Rush University Medical Center, Chicago Institute of Neurosurgery and Neuroscience, Chicago, Ill (8) PI: Demetrius Lopes MD. Central DuPage Hospital, Winfield, Ill (7) PI: Harish Shownkeen, MD, Co-PI: Henry Echiverri, MD, Fred Nour, MD, Avi Mazumdar, MD. Riverside Methodist Hospital, Columbus, Ohio (6) PI: Ronald Budzik, MD, Co-PI: Peter Pema, MD. Swedish Medical Center, Denver, Colo (5) PI: Don Frei, MD, Co-PI: Daniel Huddle, DO, Richard Bellon, MD. Forsyth Radiological Associates, Winston-Salem, NC (5) PI: Donald Heck, MD, Co-PI: Robert Ferguson, MD. Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, Ariz (5) PI: Cameron McDougall, MD, Co-PI: Murray Flaster, MD, PhD, James Frey, MD, Felipe Albuquerque, Marc Malkoff, MD. Medical College of Wisconsin, Milwaukee, Wisc (5) PI: Osama Zaidat, MD. Ospedale Maggiore Policlinico IRCCS-Milano, Italy (4) PI: Vincenzo Branca, MD. St Luke’s Hospital, Kansas City, Mo (3) PI: Naveed Ahktar, MD, Co-PI: Marilyn Rymer, MD. University of West Virginia Medical Center, Va (The University of West Virginia Medical Center, with Dr Ansaar Rai as PI, enrolled 3 patients into the trial but the local Institutional Review Board withdrew approval during patient follow-up for site compliance issues unrelated to safety.) (3) PI: Ansaar Rai, MD, Co-PI: Claudette Brooks, MD, Jeffrey Carpenter, MD, Teppe Popovich, MD. University of Iowa, Iowa City, Iowa (1) PI: John Chaloupka, MD. Florida Hospital, Orlando, Fla (1) PI: Frank Hellinger, MD. Cleveland Clinic Foundation, Ohio (1) PI: Peter Rasmussen, MD, Co-PI: Thomas Masaryk, MD, David Fiorella, MD, Henry Woo, MD. Maimonides Medical Center, Brooklyn, NY (1) PI: Steven Rudolph, MD. Hartford Hospital, Hartford, Conn (1) PI: Gary Spiegel, MD, Co-PI: Isaac Silverman, MD, Stephen Ohki, MD, Joao Gomes, MD.
Sources of Funding
The study was sponsored and funded by Penumbra Inc. A CEC adjudicated adverse events and an independent angiographic core laboratory analyzed angiographic data. Safety data were reviewed on an ongoing basis by an independent Data Safety Monitoring Board with an independent statistician. The study sponsor worked with stroke experts to design the trial, choose the investigators, control the allocation schedule, and monitor, analyze, interpret, and present the data. The trial design, including study end points, sample size, time of follow-up, and other logistics such as use of the core laboratory, CEC, and Data Safety Monitoring Board, were reviewed a priori by the US FDA. The sponsor could not suppress publication of the report even if the results were negative or detrimental to the product under study.
S.P.S. is a full-time employee of Penumbra Inc. A.B. is the Chairman, Founder, and Chief Medical Officer of Penumbra, Inc.
- Received December 22, 2008.
- Revision received April 24, 2009.
- Accepted May 6, 2009.
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