Methodology of the Interventional Management of Stroke (IMS) III Trial

SUMMARY

RATIONALE

The IMS I and II pilot trials demonstrated that the combined intravenous (IV) and intra-arterial (IA) approach to recanalization may be more effective than standard IV rt-PA (Activase®) alone for moderate-to-large (NIHSS ≥10) strokes, and with a similar safety profile.

AIMS

The primary objective of this NIH-funded, Phase III, randomized, multi-center, open-label clinical trial is to determine whether a combined IV/IA approach to recanalization is superior to standard IV rt-PA alone when initiated within three hours of acute ischemic stroke onset. The IMS III Trial will develop and maintain a network of interventional centers to test the safety, feasibility, and potential efficacy of new FDA-approved catheter devices as part of a combined IV/IA approach to recanalization as the IMS III Study progresses. A secondary objective of the IMS III Trial is to determine the cost-effectiveness of the combined IV/IA approach as compared to standard IV rt-PA. Trial enrollment began in July of 2006.

DESIGN

A projected 900 subjects with moderate-to-large (NIHSS ≥10) ischemic strokes between ages 18–80 will be enrolled over the next 5 years at 40+ centers in the United States and Canada. Patients must have IV treatment initiated within three hours of stroke onset inn both arms. Subjects will be randomized in a 2:1 ratio with more subjects enrolled in the combined IV/IA group. The IV rt-PA alone group will receive the standard full dose (0.9 mg/kg, 90 mg max [10% as bolus]) of rt-PA intravenously over an hour. The combined IV/IA group will receive a lower dose of IV rt-PA (~ 0.6 mg/kg, 60 mg max) over 40 minutes followed by immediate angiography. If a treatable thrombus is not demonstrated, no IA therapy will be administered. If an appropriate thrombus is identified, treatment will continue with either the Concentric Merci® thrombus-removal device, infusion of rt-PA and delivery of low-intensity ultrasound at the site of the occlusion via the EKOS® Micro-Infusion Catheter, or infusion of rt-PA via a standard micro-catheter. If IA rt-Pa therapy is the chosen strategy, a maximum of 22 mg of IA rt-PA may be given. The choice of IA strategy will be made by the treating neurointerventionalist. IA treatment must begin within 5 hours and be completed within 7 hours of stroke onset.

STUDY OUTCOMES

The primary outcome measure is a favorable clinical outcome, defined as a modified Rankin Score (mRS) of 0–2 at 3 months. The primary safety measure is mortality at 3 months and symptomatic ICH within the 24 hours of randomization.

INTRODUCTION

Dating back to the NINDS pilot trials of intravenous(IV) rt-PA, acute stroke trial experience has shown that it is not enough to open occluded blood vessels; we must strive to open them quickly.^1–4 However, even after ultra-early thrombolytic therapy, patients with moderate-to-large strokes (NIHSS≥10) frequently have persistent major arterial occlusions and poor outcomes.^{5, 6} In the NINDS tPA Study, only 17% of patients with NIHSS ≥20 treated with IV rt-PA had mild or no disability (modified Rankin Score 0–1).⁷

A combined IV and intra-arterial(IA) approach to acute ischemic stroke therapy was designed to offer rapidly initiated IV therapy, followed by additional titrated local IA therapy, to patients with moderate-to-large strokes (NIHSS≥10). The goal was to achieve higher rates of early, successful reperfusion in a widely accessible manner. This approach has been tested in clinical trials of over 200 patients, starting with the Emergency Management of Stroke (EMS) pilot trial from 1994 to 1995, followed by the Interventional Management of Stroke (IMS) I trial in 2001, the IMS II trial from 2003 to 2006, and several additional cohorts.^8–13 In EMS and IMS I, subjects were given low-dose IV rt-PA (0.6 mg/kg) followed by additional rt-PA (up to 22 mg) intra-arterially via standard microcatheter. As shown in Tables 1 and 2, data suggested that the combined approach to recanalization may be more effective than standard IV rt-PA (Activase®) alone for moderate-to-large (NIHSS ≥10) strokes, while maintaining a similar safety profile.

Table 1.

Comparative Efficacy in Clinical Trials of the IV/IA Approach

	IMS I (n=80)	ODDS RATIO* IMS I vs NINDS (95% CI)		IMS II (n=81)	ODDS RATIO* IMS II vs NINDS (95% CI)		NINDS rt-PA [NIHSS ≥10, age ≤ 80] (n=182)	NINDS placebo [NIHSS ≥10, age ≤ 80] (n=211)
		NINDS Placebo	NINDS rt-PA		NINDS Placebo	NINDS rt-PA
Baseline NIHSS score, median	18	--	--	19	--	--	17	17
3-mo mRS 0–1 (%)	24 (30)	2.26 (1.15, 4.47)	1.00 (0.51, 1.96)	27 (33)	2.78 (1.46, 5.31)	1.36 (0.72, 2.56)	59 (32)	38 (18)
3-mo mRS 0–2 (%)	34 (43)	2.18 (1.20, 3.99)	1.28 (0.70, 2.33)	37 (46)	2.82 (1.54, 5.16)	1.74 (0.95, 3.19)	71 (39)	59 (28)
3-mo NIHSS ≤1	22 (28)	2.51 (1.21, 5.18)	1.45 (0.73, 2.90)	22 (27)	2.84 (1.40, 5.73)	1.85 (0.92, 3.70)	45 (25)	31 (15)
3-mo NIHSS ≤2	25 (31)	2.11 (1.08, 4.13)	1.08 (0.57, 2.06)	27 (33)	2.66 (1.38, 5.12)	1.47 (0.78, 2.77)	60 (33)	42 (20)
3-mo Barthel Index 95–100	37 (46)	2.17 (1.20, 3.91)	1.39 (0.76, 2.54)	43 (53)	3.24 (1.80, 5.85)	2.29 (1.24, 4.23)	76 (42)	63 (30)

^*Adjusted for age, baseline NIHSS, and time-to-treatment

Table 2.

Comparative Safety in Clinical Trials of the IV/IA Approach

	IMS I (n=80)	IMS II (n=81)	NINDS rt-PA [NIHSS ≥10, age ≤ 80] (n=182)	NINDS placebo [NIHSS ≥10, age ≤ 80] (n=211)
Symptomatic ICH (%)	5 (6)	8 (10)	12 (7)	2 (1)
Mortality (%)	13 (16)	13 (16)	39 (21)	50 (24)

Since the inception of the combined IV/IA thrombolytic approach, two mechanical devices were cleared by the FDA for use during IA revascularization procedures based on nonrandomized studies (Figure 1). Based on two pivotal trials, the Concentric L5, X5, and X6 Merci® Retrievers received FDA clearance for thrombus removal in patients with acute ischemic stroke who are ineligible for rt-PA or fail thrombolysis.^{14, 15} The EKOS® Micro-Infusion System was studied in the IMS II trial.¹² This system (which includes low-energy ultrasound administration) was issued a substantial equivalence determination by the FDA for the administration of contrast into the neurovasculature. Both devices add to the armamentarium of acute stroke IA therapy and, therefore, were incorporated into the design of the IMS III trial.

Figure 1.

FDA-Approved Acute Stroke Revascularization Devices

As an interventional approach to cerebral revascularization becomes increasingly available and utilized throughout the world, it becomes critical to establish its benefit in the setting of large-scale Phase III clinical trials.

METHODS

Design

The IMS III trial is a Phase III, NIH U01-funded, randomized, multi-center, open-label clinical trial coordinated by the University of Cincinnati and the Data Coordination Unit (DCU) at the Medical University of South Carolina in collaboration with the University of Calgary. The primary objective of the trial is to determine whether a combined IV/IA approach (0.6 mg/kg IV rt-PA followed by intra-arterial therapy) to recanalization is superior to standard IV rt-PA alone when initiated within three hours of acute ischemic stroke onset in subjects with moderate-to-severe strokes (NIHSS≥10). The trial is designed to test the hypothesis that there is an overall absolute difference of 10% in the favorable outcome (mild or no disability as measured by a modified Rankin Score of 0–2) for subjects treated with the combined IV/IA approach as compared to those treated with standard IV rt-PA. See Figure 2 for overall trial design.

Figure 2.

IMS III Trial Design

A secondary objective of the IMS III trial is to determine the cost effectiveness of the combined IV/IA approach as compared to standard IV rt-PA as measured by differences in utilization of resources and quality of life over 12 months after the stroke between the two treatment arms of the trial. The methodology for this secondary objective is discussed in detail in the accompanying manuscript.

An additional secondary objective of this trial is to develop and maintain a network of interventional centers to test the safety, feasibility, and potential efficacy of new mechanical devices as part of a combined IV/IA approach to recanalization as the IMS III Study progresses.

Patient Population

A maximum of 900 subjects with moderate-to-large (NIHSS ≥10) ischemic stroke between ages 18–80 will be enrolled from 42+ centers in the United States and Canada. In order to be eligible for the trial, subjects must have moderate-to-large strokes (baseline NIHSS≥10) prior to initiation of IV rt-PA. In addition, IV rt-PA must be initiated within 3 hours of symptoms onset (i.e., the time at which the subject was last seen to be normal).

The protocol adheres to current medical practice regarding inclusion and exclusion criteria for revascularization therapies with only a few exceptions. Specifically, subjects older than 80-years-old have been excluded at this time due to possibly increased ICH rates based on prior IV and IA studies.⁸ However, this population may still benefit from combined IV/IA therapy overall. Additional notable exclusions include seizure at stroke onset, which precludes knowledge of the baseline NIHSS score; ongoing hemodialysis or peritoneal dialysis, due to possibly increased ICH risk based on the IMS II trial; and hyperglycemia greater than 400 mg/dL (22 mmol/L), based on increased ICH risk.

Imaging criteria for exclusion are consistent with the NINDS tPA Stroke Trial. Specifically, patients with large regions of clear hypodensity (i.e., darker than white matter and brighter than CSF) on CT scan, such as greater than one-third of the middle cerebral artery vascular territory, are excluded. An ASPECTS of ≤< 4 can be used as a guideline when evaluating >1/3 region of territory involvement.

However, sulcal effacement and/or loss of grey-white matter differentiation alone are not contraindications for treatment.

The complete list of inclusion and exclusion criteria is in Table 3.

Table 3.

IMS III Inclusion and Exclusion Criteria

Clinical Inclusion Criteria Age18 through 80 years (i.e., candidates must have had their 18th birthday, but not had their 81st birthday). Initiation of IV rt-PA within 3 hours of onset of stroke symptoms. Time of onset is defined as the last time when the patient was witnessed to be at baseline (i.e., subjects who have stroke symptoms upon awakening will be considered to have their onset at beginning of sleep). An NIHSS ≥ 10 at the time that IV rt-PA is begun. Clinical Exclusion Criteria History of stroke in the past 3 months. Previous intra-cranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arteriovenous malformation. Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT scan is normal. Hypertension at time of treatment; systolic BP > 185 or diastolic > 110 mm Hg; or aggressive measures to lower blood pressure to below these limits are needed. Presumed septic embolus, or suspicion of bacterial endocarditis Presumed pericarditis including pericarditis after acute myocardial infarction. Suspicion of aortic dissection Recent (within 30 days) surgery or biopsy of parenchymal organ. Recent (within 30 days) trauma, with internal injuries or ulcerative wounds. Recent (within 90 days) severe head trauma or head trauma with loss of consciousness. Any active or recent (within 30 days) hemorrhage. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; or oral anticoagulant therapy with INR > 1.7 or institutionally equivalent prothrombin time Females of childbearing potential who are known to be pregnant and/or lactating or who have positive pregnancy tests on admission. Baseline lab values: glucose < 50 mg/dl or > 400 mg/dl, platelets <100,000, or Hct <25 Patients that require hemodialysis or peritoneal dialysis Patients who have received heparin within 48 hours must have a normal partial thromboplastin time (PTT) to be eligible. Subjects with an arterial puncture at a non-compressible site or a lumbar puncture in the previous 7 days. Patients with a seizure at onset of stroke Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations. Other serious, advanced, or terminal illness. Any other condition that the investigator feels would pose a significant hazard to the patient if Activase® (Alteplase) therapy is initiated. Current participation in another research drug treatment protocol (patient cannot start another experimental agent until after 90 days). Informed consent is not or cannot be obtained. For example, obtunded patients are not automatically excluded from the study. However, if the next of kin or legal guardian (i.e., the individual legally empowered in the state where the consent is obtained) cannot provide consent, randomization and entry into the study could not proceed. Imaging Exclusion Criteria High density lesion consistent with hemorrhage of any degree. Significant mass effect with midline shift. Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline imaging. An ASPECTS of ≤4 can be used as a guideline when evaluating >1/3 region of territory involvement. Sulcal effacement and / or loss of grey-white differentiation alone are not contraindications for treatment. CT evidence of intraparenchymal tumor

Randomization

Subjects are randomized in a 2:1 ratio with more subjects assigned to the combined IV/IA group. This randomization regimen was chosen based on pilot data suggesting a higher rate of favorable clinical outcome in the combined IV/IA group in the IMS I and II trials as compared to comparable historical controls from the NINDS rt-PA Stroke Trial. In addition, this randomization scheme is likely to better maintain participation of neuro-interventionalists in the IMS III trial.

Design and implementation of the randomization scheme is conducted by the DCU. The randomization scheme uses a combination of minimization and biased coin design to ensure a 2:1 (IV/IA: IV only) treatment group distribution within each baseline NIHSS score stratum (10–20 or ≥20), each performance site, and throughout the overall study.

Randomization is implemented using a combination of web-based minimization+biased coin scheme and sealed randomization envelopes placed at each clinical site. A patient is randomized by opening a pre-specified sealed envelope that contains the treatment assignment. The pre-specification of the envelope is done through the web within 8 hours after the previous patient is randomized and his/her enrollment data are entered into the database via the study website. This system was designed to allow for rapid randomization since it does not require a phone call, fax back system, or access to a website prior to treatment.

Treatment

One of the guiding principles of the IMS III trial is rapid initiation of thrombolytic therapy to an eligible subject to provide maximal benefit. To minimize any delay in the administration of a proven effective therapy (i.e., IV rt-PA), the standard dose of open-label IV rt-PA (0.9 mg/kg; 90 mg maximum) can be initiated prior to enrollment and randomization in the trial if standard eligibility criteria are met. In addition, the IV rt-PA can be initiated in a patient who cannot provide informed consent for the study and for whom an authorized legal representative is not yet available (standard of care).

Randomization can be accomplished at any time prior to completion of 40 minutes of the IV rt-PA infusion (approximately two-thirds of the 0.9 mg/kg dose). This allows time to complete the determination of trial eligibility, confirm interventional staff availability, obtain consent/HIPAA authorization from patient and/or legal representative, and identify the randomization assignment. If the patient and/or authorized legal representative cannot provide informed consent for participation or the subject cannot be successfully randomized into the trial prior to completion of 40 minutes of IV rt-PA infusion, the remainder of the 0.9 mg/kg standard dose of rt-PA can be completed within the one hour. This patient would not be included as a participant in the IMS III Study and not followed as an intent-to-treat subject. A subject is considered to be in the IMS III Trial only when the sealed randomization envelope is opened.

If the patient is entered in the trial and randomized to the IV rt-PA alone group, he/she will receive the full dose (0.9 mg/kg, 90 mg max) of rt-PA intravenously over an hour, as FDA-approved standard of care.

The combined IV/IA group will open-label rt-PA over 40 minutes only instead of one hour (~0.6 mg/kg, 60 mg max) and then undergo immediate angiography. If a thrombus is not demonstrated, no additional treatment (IA rt-PA or mechanical devices) is provided. If an appropriate thrombus is identified, treatment continues with either the Concentric thrombus-removal device, infusion of rt-PA with low-energy ultrasound at the site of the thrombus via the EKOS Microinfusion Catheter System, or infusion of rt-PA via a standard micro-catheter. The choice of approach is at the discretion of the treating neurointerventionalist based upon location and extent of lesion and vascular anatomy, documented prior experience and training with Concentric or EKOS catheters, and documented instructions for use of the various catheters. However, use of both the Concentric and EKOS catheters in the same patient is not permitted. The rt-PA used for intra-arterial treatment is provided as an investigational drug. No more than 22 mg of rt-PA will be administered intra-arterially, and IA treatment must begin within five hours of onset and be completed within 7 hours. See Figure 3 for IA Treatment Protocol.

Figure 3.

IA Treatment Protocol

Primary Outcomes

The efficacy of the IV/IA approach, compared to IV rt-PA therapy, will be tested using the primary outcome measure of a modified Rankin Scale (mRS) at 3 months from randomization. A score of 0–2 will be considered to be the favorable outcome. An mRS score of 0–2 was selected for assessing outcome of moderate-to-severe strokes based on PROACT II, IMS I, and IMS II results.^{11, 12, 16} The measure of a favorable clinical outcome will also be analyzed in two pre-specified subgroups based on stroke severity, consisting of those with a baseline NIHSS of 10–19 and those with a baseline NIHSS of ≥ 20.

The primary safety measures will be mortality at 3 months and symptomatic ICH within 24 hours after stroke onset.

Secondary Outcomes

The IMS III Trial will also evaluate the effectiveness of the combined IV/IA approach compared to the IV rt-PA therapy alone by a number of secondary outcome measures including: (1) the Barthel Index, Glasgow Outcome Scale, NIHSS, EuroQol EQ-5D, and Trail Making Test Parts A and B at 3 months; (2) an improved early response to treatment as determined by an NIHSS of 0–2 at 24 hours; (3) a CT angiography assessment of intracranial vascular patency at 24 hours (both treatment groups); (4) the volume of cerebral infarction as measured by a CT scan at 24 hours from onset; (5) change in Alberta Stroke Program Early CT Score (ASPECTS) score from baseline to 24 hours on CT scan; and (5) the rate of TICI Grade II or III perfusion flow and recanalization of the primary arterial occlusion at completion of angiography (combined IV/IA group only).

Secondary safety measures will include: (1) the proportion of subjects with Type II parenchymal intracerebral hematomas within the first 24 hours; and (2) the incidence of any asymptomatic hemorrhage within the first 24 hours.¹⁷

Additionally, the following measures of safety will also be monitored: (1) incidence and severity of non-intracerebral bleeding complications; (2) incidence and severity of non-bleeding SAEs; (3) incidence of clinically significant abnormal (as determined by the Clinical Center PI) laboratory values at 24 hours; (4) changes in hemoglobin and hematocrit from baseline to 5 day or discharge; (5) incidence of blood and/or blood products transfusion of 3 or more units during hospitalization; and (6) incidence and severity of procedure and device related complications (i.e., vessel perforation, clinically significant groin complications, etc.) in the IV/IA rt-PA group.

Data and Safety Monitoring

An independent Data Safety and Monitoring Board, consisting of clinicians familiar with the treatment of stroke, biostatisticians, a neuro-interventionalist, and other experts, has been established by NINDS to monitor the progress of the trial. Additionally, two stroke neurologists have been appointed as internal and external safety monitors. The Internal Safety Monitor will review safety data on an ongoing basis, including monitoring the trend in serious adverse outcome events and submitting FDA Medwatch reports. The External Safety Monitor, an independent and experienced neurologist, will review all serious life-threatening bleeding events during this study and be the final adjudicator of intracranial hemorrhage endpoints (symptomatic or asymptomatic and the relationship to study intervention) when there is disagreement between the local site and the Internal Medical Monitor. This is the same methodology used by the NINDS rt-PA Stroke Trial and IMS I and II Pilot Studies.

Regionally-based, industry-experienced, independent contracted clinical research monitors will perform on site data verification for the trial. The initial monitoring visit at a performance site will take place after the first IV/IA treatment subject is enrolled at a site. Thereafter, each SAE will be monitored and each site will be visited no less than once each year during the trial.

All de-identified imaging data will be sent to the Clinical Coordinating Center at the University of Cincinnati for standardized CD archiving and data blinding (if needed). CT and CTA imaging will then be transferred to the Imaging Analysis Center in Calgary for central interpretation by a blinded three-member consensus panel. To expedite safety reporting, all acute CT data received from a clinical center will initially be reviewed by a blinded central reader at the University Cincinnati. All angiographic data will be reviewed by two independent readers, and a third reader will provide final adjudication as needed.

Sample Size

The total sample size of 900 was determined based on an anticipated effect size of 10% (the absolute difference between the IV rt-PA and IV/IA rt-PA arms in the proportion of subjects with favorable outcomes). Specifically, we assumed that the proportion of IV rt-PA proportion with favorable clinical outcome would be 40% (obtained from the NINDS rt-PA Study), the 2:1 ratio of IV/IA to IV only group assignment, and Type I and Type II error probabilities of 0.05 and 0.20,respectively, and three pre-specified interim analyses. Since the intent-to-treat principle will be applied to the analysis, the sample size of 900 includes inflation by 1.03 to safeguard against dilution of the effect size by patients lost-to-follow-up and/or treatment cross-over in approximately 1–3% of cases.

Statistical Analyses

The set of statistical hypotheses for the overall sample is: H₀: π_IV = π_IV/IA versus HA: π_IV ≠ π_IV/IA, where π_IV and π_IV/IA are the proportion of subjects with favorable outcome (mRS of 0–2 at 3 months after randomization) for the IV and IV/IA arms, respectively. The primary efficacy hypotheses will be tested with the Cochran-Mantel-Haenszel (CMH) test adjusting for the dichotomized baseline NIHSS score (<20 or ≥20). The statistic will be tested at alpha level of 0.05. Three interim analyses will occur after approximately 225 (25% of 900), 450 (50%), and 675 (75%) subjects complete the 3-month mRS assessment and tested at appropriate nominal alpha levels that ensure overall alpha level of 0.05.

Ideally, all stratification variables should be accounted for in the analysis of primary efficacy outcome measure. For the IMS III Trial, the stratification variables are the dichotomized baseline NIHSS (10–19 versus >= 20) and Clinical Center Performance Site, both assumed to be fixed effects. Due to the large number of participating Clinical Centers (approximately 42), a statistical analysis model with Clinical Center as a fixed effect would yield unstable estimates of the treatment effect. Therefore, the Clinical Center effect will be omitted in the primary analysis of the dichotomized mRS score at 3 months. However, as a secondary analysis, we will re-analyze the primary efficacy outcome variable with Clinical Center as a random effect and the treatment group and baseline NIHSS category as fixed effects in the mixed effects model for the overall sample.

For other exploratory analyses of the primary outcome variable, the dichotomized mRS outcome will be assessed for treatment differences adjusting for a variety of covariates deemed clinically or prognostically important, such as age, time between symptom onset and randomization, and baseline NIHSS score. Each covariate will be assessed individually first with a model that includes interaction effect with the treatment (IV only or IV/IA). If significant interaction (p<0.10) is observed, subgroup analyses will be considered. Quantitative and qualitative interaction between the treatment and each covariate will also be visually assessed by graphical methods.

An exploratory hypothesis of clinical interest for the primary outcome measure is the differential effect of various IA devices. Generalized linear regression analysis of the dichotomized mRS score at 3 months will be conducted with dummy variables representing different devices. Because of the 2:1 randomization ratio for the treatment assignment, we anticipate a sample size of approximately 600 for this analysis.

Analyses of other secondary clinical outcome, imaging, and safety measures will be conducted at the completion of the trial. Inferences made from these analyses will be supportive evidence (or lack thereof) of the effectiveness of IV/IA therapy rather than primary evidence.

To compare the safety of the IV/IA approach and IV rt-PA therapy, non-inferiority hypothesis tests for the two primary safety parameters – mortality at three months and the incidence of symptomatic ICH within the first 24 hours will be conducted. The margin of non-inferiority (δ) chosen will be tentatively set at absolute 5%. Furthermore, these safety outcomes will be compared between the treatment groups, adjusting for possible confounders, such as baseline NIHSS and time from symptom onset to randomization in a regression model.

At the end of the study, the cumulative incidences of selected adverse events will be compared between the two treatment groups using Fisher’s exact test. Each of the secondary outcomes and exploratory analyses will be tested at the alpha level of 0.01 in order to nominally control the Type I error probability inflation.

Data Management

An electronic copy of the CRF is made available to the Clinical Centers prior to initiation of the study to be used as worksheets for capturing data for the Trial. The study database, WebDCU™ System, has been developed in Microsoft SQL Server based on the approved CRFs. This system allows for a web-based data entry and management. The data are captured and entered (single keyed) at the Clinical Centers via the web interface. The data are managed (including data queries) by the DCU using a secured Trial website. During the design of the database, automated consistency checks and data validation rules were programmed to check for potential data errors, including missing required data, data out of pre-specified range, data conflicts and disparities within and among the CRFs. The validation procedure is implemented and any changes made on the website have a full audit trail. All data items that fail the programmed consistency checks are queried via the data clarification request (DCR) process initiated by the DCU. The DCRs are generated, communicated between the DCU and the Clinical Centers, and resolved on the secured study website. In addition to the study database, the DCU provides the Clinical Center staff access (via password) to a standard set of web-enabled tools, including subject visit calendar, accrual status, CRF completion status, and outstanding DCR status pertaining to their respective Centers. In addition, these tools allow the staff to receive regular updates on overall study status, new external information relevant to the Trial, Committee meetings calendar, etc.

Study Organization and Funding

The participating units in this collaborative clinical trial will include at least 42 individual clinical centers, the Clinical Coordinating Center and the Angiographic Imaging Center at the University of Cincinnati (CCC), the IMS III Data Coordination Unit at the Medical University of South Carolina, the CT Imaging Center at the University of Calgary, Canadian Drug Distribution and Coordination Center at the University of Calgary, the Scientific Advisory Committee, the Data and Safety Monitoring Committee, and the NINDS Division of Stroke and Trauma. See Figure 4.

Figure 4.

IMS III Trial Administrative Core

The IMS III trial is funded as a collaborative U01 trial by the NIH/NINDS. Johnson and Johnson/Cordis Neurovascular, EKOS Corporation, and Concentric Medical supply catheter devices used in the IMS III trial. Genentech, Inc. has agreed to supply study medication for IA treatment in the IMS III Study. As the trials proceeds, if new revascularization strategies become FDA-approved, other companies could become involved in the conduct of the IMS III trial.

SUMMARY

The primary objective of this NIH-funded, Phase III, randomized, multi-center, open-label clinical trial is to determine whether a combined IV/IA approach to recanalization is superior to standard IV rt-PA alone when initiated within three hours of acute ischemic stroke onset in subjects with moderate-to-severe strokes (NIHSS≥10). The IMS III Trial will develop and maintain a network of interventional centers to test the safety, feasibility, and potential efficacy of new FDA-approved catheter devices as part of a combined IV/IA approach to recanalization as the IMS III Study progresses. Trial enrollment began in July of 2006. As of submission in February of 2007, 21 sites were actively screening and 20 patients were enrolled.