Safety and Efficacy of Solitaire Stent Thrombectomy

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Index:
Table I -Summary of individual trial characteristics Table II-III -Patient and procedural characteristics for sensitivity analyses

Table IV-V -Patient outcomes in the sensitivity analyses
Tables VI-VIII -Patient outcomes for those treated with alteplase within 0-3 hours and 3-4.5 hours after stroke onset   PH2 + ≥4 point increase NIHSS NIHSS -National Institutes of Health Stroke Scale, mTICI -modified Treatment in Cerebral Ischaemia grading of angiographic reperfusion (2b is >50% reperfusion of the affected territory), ICA -internal carotid artery, MCA -middle cerebral artery: M1 first segment, M2 second segment. CT -non-contrast computer tomography, CTA -CT angiography, mCTA -multiphase CT angiography for collateral scoring, CTP -CT perfusion, MRImagnetic resonance imaging, MRA -magnetic resonance angiography. * ESCAPE reported 72% revascularization using Thrombolysis in Cerebral Infarction (TICI) scale where 2b is >66% reperfusion of the affected territory -this was re-scored defining mTICI 2b>50% for this meta-analysis. † SWIFT PRIME upper limit age 85 at trial start; after 1 st 72 patients amended to upper limit age 80. Non-contrast CT ASPECTS -Median (Inter-quartile range) 9 (7-10) 9 (7-10) Time (min) from stroke onset to arterial access, median (IQR) N/A 235 (164-301)  (0) to death (42) No statistically significant differences between groups * mTICI: modified Treatment in Cerebral Ischemia classification, as assessed by individual trial core laboratory, i.e. TICI 2b >50%. Scale ranges from no flow (0) to normal flow (3). 7    Figure I -Distribution of modified Rankin scores at 90 days in the sensitivity analysis 1: SWIFT PRIME, EXTEND-IA, REVASCAT and ESCAPE (excluding those in whom a device other than Solitaire was used first). Panel A) overall results B) comparing age dichotomized at 70 years C) comparing age dichotomized at 80 years D) comparing those who did or did not receive intravenous alteplase prior to endovascular stent thrombectomy. Figure III -Treatment effect in pre-defined subgroups (Forest plot) for sensitivity analysis 1: SWIFT PRIME, EXTEND-IA, REVASCAT and ESCAPE (excluding those in whom a device other than Solitaire was used first). Odds ratios with 95% confidence intervals, analyses adjusted for age, sex, baseline stroke severity, site of occlusion, intravenous alteplase treatment, ASPECTS score, and time from onset to randomization).

Figure IV
-Treatment effect in pre-defined subgroups (Forest plot) for sensitivity analysis 2: SWIFT PRIME, EXTEND-IA and REVASCAT. Odds ratios with 95% confidence intervals, analyses adjusted for age, sex, baseline stroke severity, site of occlusion, intravenous alteplase treatment, ASPECTS score, and time from onset to randomization).
(Solitaire-only trials) CONFIDENTIALITY: The information in this document is confidential and is the property of the SEER Working Group. The information may be provided only to Investigators, sub-Investigators, and appropriate trial personnel, members of the Institutional Review Board/Institutional Ethics Committee (IRB) and personnel of the authorities to whom it is submitted. This Statistical Analysis Plan may not be photocopied or discussed with third parties not involved in the trial without the prior written authorization from the SEER Working Group.

LIST OF ABBREVIATIONS AND DEFINITIONS
Abbreviation Abbreviated Term Definition AAE Anticipated Adverse Event Any decline away from the patient's baseline health, whether related to the investigational device, the procedure or the disease that is predefined in the Investigational Plan, CRFs, and Instructions For Use.

ADE Adverse Device Effect
Any untoward and unintended response to a medical device including insufficiencies or inadequacies in instructions for use or deployment of the device.

AE Adverse Event
Any decline away from the patient's baseline health. Any decline from the patient's pre-treatment condition that occurs during the course of the clinical Study, after study enrollment, whether related to the investigational device, the procedure or the disease. Treatment includes all investigative or commercially approved products administered according to the Investigational Plan.

Asymptomatic Intracranial Hemorrhage
Any intracranial hemorrhage within 24 hours not meeting the criteria for symptomatic intracranial hemorrhage.

AIS Acute Ischemic Stroke
Focal symptoms due to cerebral infarction from an arterial occlusion.

CEC Clinical Events Committee
Independent committee responsible for the review and validation of all complications that occur over the course of the Study.

Digital Imaging and Communications in Medicine
The standard foundation for imaging and image management; A global information-technology standard designed to ensure the interoperability of systems used to produce, store, display, process, send, retrieve, query, or print medical images and derived structured documents.

DSMB Data Safety and Monitoring Board
An independent data monitoring committee, established by the sponsor, to assess at intervals, the progress of a clinical trial, the safety data and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify or stop a trial.

DWI Diffusion Weighted Imaging
Imaging obtained using magnetic resonance sequences that measure diffusion properties of water within tissue. eCRF Electronic Case Report Form An electronic document designed to record all of the protocol requested information to be reported to the sponsor on each study patient. eCRFs are "living documents" in the respect that new information on the patient is continually gathered throughout the study. FR Flow Restoration Restore flow through a vessel that is occluded by blood clot.

GCP Good Clinical Practice
The regulations enforced in the US by the FDA's bioresearch monitoring program for medical devices, consisting of 21 CFR 812, -50 and -56. The GCP requirements are also stated in "Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, ICH, April 1996: A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported are credible and accurate, and that the rights, integrity and confidentiality of trial patients are protected. Health Insurance Portability and Accountability Act of 1996. Title II of the Act, "Administrative Simplification" refers in large part to federal privacy rules that require health care providers and others to obtain written authorization from patients or their legally authorized representatives before using or disclosing their "Protected Health Information" (PHI) for any purposes other than treatment, billing, quality assurance and education.

ICF Informed Consent Form
The written, signed and dated document that provides objective evidence of the process by which a patient voluntarily confirms his or her willingness to participate in a particular study, after having been informed of all aspects of the trial that are relevant to the patient's decision to participate (21 CFR 50).

International Conference for Harmonization
An Organization whose main purpose is to achieve greater harmonization to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.

IDE Investigational Device Exemption
An approved IDE permits a device that would otherwise be required to comply with a performance standard or would require a premarket approval to be shipped lawfully for the purpose of conducting investigations of that device (21 CFR 812).

I/E Inclusion/Exclusio n Criteria
A list of conditions that would include or exclude a patient from enrolling/participating in a clinical study as outlined in the study protocol.

IEC Independent Ethics Committee
An independent body, constituted of medical/scientific professionals and nonmedical/nonscientific members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human patients involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favorable opinion on the trial protocol, the suitability of the investigator(s), facilities and the methods and material to be used in obtaining and documenting informed consent of the trial patients.

INR International Normalized Ratio
Ratio that measures the time it takes for blood to clot and compares it to a reference normal value.

IP Investigational Plan
The clinical protocol and associated documents whose required composition is described in 21 CFR 812.25.

IRB Institutional Review Board
Any board, committee, or other group formally designated by an institution to review biomedical research involving patients and established, operated and functioning in conformance with 21 CFR 56.

International Organization for Standardization
International standard-setting body composed of representatives from various national standards organizations.

ITT Intent-to-Treat
The ITT population includes all patients with data for a given endpoint and are assessed according to randomized assignment regardless of the treatment actually received IV t-PA

Intravenous Tissue Plasminogen Activator
Medical treatment of myocardial infarction with ST-elevation (STEMI), acute ischemic stroke (AIS), acute massive pulmonary embolism, and central venous access devices (CVAD) administered intravenously. t-PA is an enzyme (serine protease) found in endothelial cells that line the blood vessels that converts plasminogen into plasmin, an enzyme responsible for blood clot breakdown.

IVRS Interactive Voice Response System
Accessed by telephone, it is a system that randomly assigns the patient to a treatment arm based on the pre-determined randomization algorithm.

IWRS Interactive Web Response System
Accessed by internet, it is a system that randomly assigns the patient to a treatment arm based on the pre-determined randomization algorithm.

PWI Perfusion weighted imaging
Imaging obtained using contrast that measures the brain perfusion including vascular transit time, cerebral blood volume, and cerebral blood flow.

QALY Quality-adjusted life year
A measure that takes into account both the quantity and quality of life generated by healthcare interventions. It is the arithmetic product of life expectancy and a measure of the quality of the remaining life-years

RApid processing of PerfusIon and Diffusion
A system that computes quantitative perfusion maps (cerebral blood volume, CBV; cerebral blood flow, CBF; mean transit time, MTT; and the time until the residue function reaches its peak, T(max)) using deconvolution of tissue and arterial signals.

SAE Serious Adverse Event
Adverse Event that led to death or serious deterioration in the health of a patient that resulted in a life threatening illness or injury, permanent impairment of a body structure or a body function, hospitalisation or prolongation of existing hospitalisation, medical or surgical intervention to prevent permanent impairment to a body structure or a body function or is a congenital anomaly/birth defect. This Statistical Analysis Plan (SAP) describes the statistical methods to be used for the analysis of the integrated safety and efficacy data from 4 randomized parallel-design studies where the objective was to treat patients presenting with an acute ischemic stroke. This plan has 5 elements: • Comparison of the baseline patient-level data across the 4 studies, • statistical analyses to evaluate safety and efficacy across the 4 studies using the analysis dataset rules from each of the individual studies, • pooling the statistical evidence across the 4 randomized studies using the analysis dataset rules from each of the individual studies, • pooling the patient-level data across the 4 randomized studies, generating an integrated database with a common set of analysis dataset rules • statistical analyses to evaluate safety and efficacy across the 4 studies using the integrated database with a common set of analysis dataset rules The tabulations and information from this SAP will provide an unbiased examination of the safety and efficacy of mechanical embolectomy relative to medical management alone. The integrated database will also allow examination of the safety and efficacy of mechanical embolectomy with the Solitaire FR device.
These analyses will be presented to the SEER committee for review, publication, and presentation. The approach used for the integration outlined in this document will also generate the requisite information to support the generation of an integrated Clinical Study Report (CSR), including the detailed descriptions of the statistical methodologies to be applied.
The structure and content of this plan provides sufficient detail to meet the requirements identified by the FDA and International Conference on Harmonization of Technical Requirements for medical devices, as well as the Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical Principles in Clinical Trials.

Study Design and Enrollment for EXTEND-IA, ESCAPE, REVASCAT AND SWIFT PRIME
The clinical trial designs and control groups were similar across the 4 studies. The source of the summarized information from each study, along with the information regarding recruitment, was ClinicalTrials.gov.
ESCAPE was a multi-center, randomized, single blind (Outcomes Assessor) parallel design study open to patients ≥18 years of age enrolled within 12 hours of last being seen normal with a baseline NIHSS > 5 at the time of randomization. Several devices were permitted to be used, with the Solitaire stent retriever used in the majority. On the advice of the DSMB, trial recruitment was halted for efficacy and the study was terminated.
EXTEND-IA was a multi-center, randomized, single blind (Outcomes Assessor) parallel design study open to patients ≥18 years of age enrolled within 4.5 hours of stroke onset. Only the EXTEND-IA / ESCAPE / REVASCAT / SWIFT PRIME Studies ISS and ISE Statistical Analysis Plan November 1, 2015 Version 1.0 Confidential Page 9 of 21 Solitaire stent retriever device was used. On the advice of the DSMB, trial recruitment was halted for efficacy and the study was terminated.
REVASCAT was a multi-center, randomized, single blind (Outcomes Assessor) parallel design study open to patients 18 to 85 years of age presenting within 8 hours of symptom onset consistent with an acute ischemic stroke. Only the Solitaire stent retriever device was used. On the advice of the DSMB, trial recruitment was halted for efficacy and the study was terminated.
SWIFT PRIME was a multi-center, randomized, single blind (Outcomes Assessor) parallel design study open to patients 18-85 years of age. Eligible patients were treated within 6 hours of the onset of stroke symptoms and within 1.5 hours from CTA or MRA to groin puncture and had a baseline NIHSS ≥ 8 and < 30 at the time of randomization. Only the Solitaire stent retriever device was used. This study was completed in January 2015.
Collectively, the primary objective of all 4 studies was the same: to evaluate the hypothesis that mechanical embolectomy is superior to medical management alone in achieving a favorable outcome based on the distribution of the modified Rankin Scale at 90 days in patients presenting with an acute large vessel ischemic stroke.
The methods for assigning patients to either mechanical embolectomy or medical management through randomization were also similar across the 4 studies regarding stratification.
For EXTEND-IA, patients were randomized to receive intra-arterial clot retrieval after IV tPA or IV tPA alone. Patients randomized to treatment were stratified for site of baseline arterial occlusion into one of three groups: Internal carotid artery (ICA), proximal middle cerebral artery (MCA -M1), or distal middle cerebral artery (MCA -M2).
For ESCAPE, patients were randomized to receive intra-arterial clot retrieval after IV tPA or IV tPA alone. The randomization was stratified based on age, baseline stroke severity (NIHSS), initial arterial lesion location, ASPECTS score, and site.
For SWIFT PRIME, patients were randomized to IV tPA alone or IV tPA plus Solitaire The randomization ratio for mechanical embolectomy or medical management was 1:1 and balanced within investigational sites and by baseline NIHSS severity (<= 17 versus >17), age (<70 years versus >=70 years at the time of randomization) and occlusion location (M1 versus all other).
The time to treatment was an important factor for inclusion in each of the 4 studies. For EXTEND-IA, patients were to be enrolled within 6 hours of stroke onset. For ESCAPE, the time to treatment had to be within 12 hours of stroke symptoms, endovascular treatment (groin puncture) within 60 minutes, target CT to first recanalization of 90 minutes. For REVASCAT, the time to treatment had to be within 8 hours of symptom onset. For SWIFT PRIME, the time to treatment had to be within 6 hours of onset of stroke symptoms and within 1.5 hours (90 minutes) from CTA or MRA to groin puncture. The schedule of assessment for each of the 4 randomized studies only fully aligned for the baseline / pre-procedure and 90 day evaluation. The post-randomization evaluations were similar in terms of timing; however, the time windows for evaluation did not completely align. Specifically, the first post-procedure assessment in SWIFT PRIME had a 27 hour +/-6 hour window (21 to 33 hours post procedure). ESCAPE defines the time point simply as 24 hours or 1 day; it is indeterminate what the exact window was; this will be quantified based on the actual data. REVASCAT had a 22 to 36 hour time window. For integration purposes, all data collected at the ~24 hour post-randomization evaluation will be integrated for the Level 1 presentation and the distributions will be compared across the 4 randomized studies. For the Level 2 presentation of the safety and efficacy results, only evaluations recorded within 21 to 36 hours of randomization will be considered.

Multiple observations for a patient within a time window
If a patient has multiple observations within a time window for the -24 hour post randomization evaluation, the value recorded closest to 24 hours will be used.

Retaining Clinical Center or Site in the Model for Analysis
In each of the 4 multicenter studies, the randomization scheme was balanced intra-center. Within each center, patients were stratified relative to a number of factors. The timing of individual examinations and the time windows are presented below.

Selection of the computational Model for Analysis
The selection of a computational model was based on our expectation about whether or not the studies shared a common effect size, and on our research goals in performing the analysis. The use of a fixed-effect model would be appropriate if we believed that the studies are functionally identical, and our goal is to compute the common effect size for the identified population, and not to generalize to other populations. Given the studies were all conducted independently and in different geographic locations, it would be unlikely that all the studies were functionally equivalent. The consensus opinion of the SEER working group was that these studies differed in ways that could impact the outcomes and therefore one should not assume a common effect size. Additionally, the goal of this analysis is to generalize to a range of scenarios. Therefore, if one did make the argument that all the studies used an identical, narrowly defined population, then it would not be possible to extrapolate from this population to others, and the utility of the analysis would be severely limited. We acknowledge the number of studies being analyzed is small and the estimate of the between-studies variance may lack precision.
In summary, a fixed-effect meta-analysis estimates a single effect that is assumed to be common to every study, while a random-effects meta-analysis estimates the mean of a distribution of effects. Study weights are more balanced under the random-effects model than under the fixedeffect model. Large studies are assigned less relative weight and small studies are assigned more relative weight as compared with the fixed-effect model. The standard error of the summary effect and the confidence intervals for the summary effect are wider under the random-effects model than under the fixed-effect model. The selection of a model must be based solely on the question of which model fits the distribution of effect sizes, and takes into account the relevant sources of error; for this reason, we believe the application of a more conservative random effects model is justified.

ANALYSIS POPULATIONS
The following populations will be considered for the integration and presentation of the data:

Enrolled Population
The Enrolled Population includes all consented patients in each of the 4 studies who were randomized, independent of the administration of tPA or the outcome of the procedure. The randomized groups for comparison will be referred to as the Standard of Care Plus Thrombectomy and Standard of Care Alone. In the analysis tables, the Standard of Care Plus Thrombectomy will be referred to as the Device Group; Standard of Care Alone will be referred to as the Control Group.
The primary analysis will be performed in the 3 trials that used only the Solitaire device (SWIFT PRIME, EXTEND-IA and REVASCAT. Two sensitivity analyses will be performed including additional data from the ESCAPE trial 1) including only those patients from the endovascular arm in which the first device actually used was Solitaire or would have been used had a target clot been still present and accessible (Solitaire intention to treat analysis), and 2) including all patients in the endovascular arm, whether or not Solitaire was used first (4 trial analysis).
Addendum 30-Dec-2015 -in response to journal reviewer's suggestion, the primary analysis was changed to be the full four trial dataset and the 3 trial analysis was instead presented as the second sensitivity analysis.
IV tPA Treated Within 3-Hours Population (in accordance with FDA label for alteplase) The IV tPA Treated Within 3-Hours Population includes all consented patients in each of the 3 populations studied who were administered IV tPA within 3 hours of the stroke symptom onset.

BASELINE INFORMATION
The demographic, physical characteristic, neurologic history and pre-procedure imaging data will be evaluated to assess the magnitude of the differences in the patients enrolled in the 4 studies. Probability values to evaluate the differences will be considered significant if the value is <0.05. The description presented below describes the method of summarization and comparison of the following factors: •

Evaluation and Integration of the Baseline Demographic Data for EXTEND-IA, ESCAPE, REVASCAT AND SWIFT PRIME
All enrolled patients from the 4 studies will be summarized with respect to age at entry into the study, Sex, ethnicity, and race. Age will be calculated as [Date of Informed Consent -Date of Birth] / 365.25 rounded down to the nearest integer. Age will be reported in years (yr) and summarized using descriptive statistics: n, arithmetic mean, standard deviation, median, range (i.e., minimum and maximum values) and compared between the randomized treatment assignments using a mixed model specifying the distribution as continuous with study and studyby-treatment as random effects. Patients with missing data that cannot be resolved will not be included in the tabulation and excluded from the summary statistics. The number and percent of patients ≤70 and > 70 and ≤80 and >80 years of age at the time of enrollment will be presented by randomized treatment assignment and study, and independent of study using counts and percentages. The proportion of patients in each mutually-exclusive category will be compared between the randomized groups using a mixed model specifying the distribution as binomial with study and study-by-treatment as random effects. Results will also be generated for the IV tPA Treated Population (Tables 1a) and the IV tPA Treated Within 3-Hours Population (Tables  1b). EXTEND-IA / ESCAPE / REVASCAT / SWIFT PRIME Studies ISS and ISE Statistical Analysis Plan November 1, 2015 Version 1.0 Confidential Page 15 of 21

Evaluation and Integration of the Baseline Physical Characteristic Data for EXTEND-IA, ESCAPE, REVASCAT AND SWIFT PRIME
All enrolled patients from the 4 studies will be presented in Table 2.0 entitled Summary of Physical Characteristics Recorded at Baseline (Enrolled Population). This table will summarize the physical characteristic data by study with respect to height (inches), weight (lbs.), BMI, and Pre-stroke mRS. Height, weight, BMI, and pre-stroke mRS will be summarized using descriptive statistics: n, arithmetic mean, standard deviation, median, range (i.e., minimum and maximum values) and compared between the randomized treatment assignments using a mixed model specifying the distribution as continuous with study and study-by-treatment as random effects.
Patients with missing data that cannot be resolved will not be included in the tabulation and excluded from the summary statistics.

TPA AND MECHANICAL THROMBECTOMY INFORMATION
Patients will be classified as having received tPA (Yes or No) and if they underwent mechanical thrombectomy (Yes or No). Specific information regarding the time to administration of tPA and the thrombectomy procedure will also be used in the logistic and random-effect models.

Evaluation of the Time to Specific Events
• Individual times will be summarized using descriptive statistics: n, arithmetic mean, standard deviation, median, range (i.e., minimum and maximum values) and compared between the randomized treatment assignments using a mixed model specifying the distribution as continuous with study and study-by-treatment as random effects. Patients with missing data that cannot be resolved will not be included in the tabulation and excluded from the summary statistics.

SAFETY INFORMATION
The assessment of safety will be based on adverse events reported within 90 days of randomization and the incidence of symptomatic ICH (intracranial hemorrhage) within 21 to 36 hours of randomization.

Assessment of the Safety Data for EXTEND-IA, ESCAPE, REVASCAT AND SWIFT PRIME
The incidence of symptomatic ICH will be defined in accordance with the definitions used in each trial.
Adverse events will be presented according to 3 time intervals: peri-procedural adverse events, adverse events reported within 30 days of randomization, and adverse events within 90 days of randomization. Peri-procedural adverse events are events that occur during the thrombectomy procedure An adverse event is defined as any decline away from the patient's baseline health. Any decline from the patient's pre-treatment condition that occurs during the course of the clinical Study, after starting treatment, whether related to the investigational device, the procedure or the disease. A serious adverse event is an event that leads to death, fetal distress, fetal death or a congenital abnormality or birth defect, and serious deterioration in the health of a patient that resulted in a life-threatening illness or injury such as a permanent impairment of a body structure or a body function, requiring in-patient hospitalization or prolongation of existing hospitalization, results in medical or surgical intervention to prevent permanent impairment to a body structure or a body function. Treatment includes all investigative or commercially approved products administered according to the Investigational Plan from each of the 4 studies.
The following information regarding each adverse event includes the date and time of onset and resolution (duration), intensity, whether it was serious, any required treatment or action taken, outcome, relationship to the investigational procedure or tPA, and whether the adverse event caused withdrawal from the study.
Mild: Patient is aware of event or symptom but event/symptom is easily tolerated.
Moderate: Patient experiences sufficient discomfort to interfere with or reduce their usual level of activity.
Severe: Significant impairment of functioning; patient is unable to carry out usual activities.
The relationship of the adverse events across the studies were defined using different scales.
For SWIFT PRIME, there were 9 coded categories: 1 =IV t-PA Related, For ESCAPE, there were 2 categories for relationship to the endovascular procedure; yes or no.
For REVASCAT, relationship to the investigational device or procedure was collected using the following 5 categories: 1=Definitive 2=Probable 3=Possible 4=Conditional 5=Not related For EXTEND-IA, relationship to the investigational device was collected using the following 5 categories: 1=Not related, 2=Unlikely, 3=Possible, 4=Probable, 5=Definite