Flow Diversion versus Traditional Endovascular Coiling Therapy: Design of the Prospective LARGE Aneurysm Randomized Trial

Design

LARGE is an international prospective multicenter trial to compare the safety and efficacy of flow diversion to traditional endovascular techniques for the treatment of anterior circulation large and giant aneurysms. Subjects will be randomized to either flow diversion or endovascular coiling (reconstructive coiling with or without adjunctive devices [stents, balloons] or deconstruction) cohorts in a 1:1 fashion and will be assessed for the primary outcome at 6 months with subsequent outcomes until 3 years from aneurysm repair. The primary objective is to show that flow diversion is noninferior to endovascular coiling at 180 days from aneurysm treatment on the primary end point by less than an absolute difference of 15%. The primary outcome is a combined efficacy and safety end point defined by greater than 90% angiographic occlusion with stable or decreased aneurysm size on cross-sectional imaging (CT or MR) at 180 days postprocedure and freedom from any major neurologic event (defined as change in NIHSS from baseline >4 points) or death at 180 days postprocedure.

Patient Population

The On-line Table shows patient eligibility criteria. Figure 1 shows the flow chart of patients through LARGE. The LARGE trial includes current flow-diversion on-label patients, with aneurysms larger than 1 cm located on the internal carotid artery below the level of the posterior communicating artery. The aneurysm must be amenable to either conventional endovascular therapy or flow diversion according to the operator's discretion. Many patients with large paraclinoid aneurysms present clinically with visual or ocular findings. If the patient's presentation includes any eye signs or symptoms, the patient will be referred for evaluation by a neuro-ophthalmologist preprocedurally.

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Fig 1.

Study flow from referral through follow-up.

Randomization

Randomization will occur in a 1:1 ratio to either flow diversion or endovascular coiling. The covariate adaptive randomization balances treatment assignment based on aneurysm location (intradural versus extradural), presence of intraluminal thrombus (“yes” versus “no”), aneurysm shape (saccular versus fusiform), prior balloon test occlusion (“yes” versus “no”), and current status of treatment groups within and across clinical sites. Once the patient is determined to meet all study eligibility criteria, covariate adaptive randomization takes place centrally via the LARGE Study Web site on the WebDCU (https://webdcu.musc.edu).

Treatment

Subjects assigned to coil embolization will undergo treatment of the target IA with endovascular coiling with FDA-approved technologies. Procedures will be performed according to the technology instructions for use. The goal of coil treatment is to completely occlude the IA. Other devices (eg, intravascular balloons [“balloon remodeling”], intravascular stents, dual catheters, etc) may be used adjunctively to deliver or direct coils into the target IA. Alternatively, deconstructive techniques with parent vessel occlusion utilizing endovascular coiling are allowed if this option is felt to be the best treatment technique for the patient. The patient must first successfully pass a balloon test occlusion before vessel occlusion.

Subjects assigned to flow diversion will undergo placement of flow diverter(s) across the target IA. The placement procedure is described briefly in Fig 1 and in more detail in the device instructions for use document. One or more flow diverters may be placed as deemed necessary by the investigator.

Aspirin and clopidrogel are used before flow diverter placement or endovascular coiling embolization. Aspirin is used for at least 1 year after endovascular coiling or flow diverter placement. Clopidogrel is used for at least 3 months after endovascular coiling embolization or flow diverter placement. Aspirin and/or clopidogrel may be used beyond (or at higher doses) than the indicated regimen, if appropriate clinically (eg, patient previously taking aspirin for coronary artery disease prophylaxis).

Primary Outcome

The primary outcome is a dual end point of efficacy and safety. Efficacy is defined as >90% angiographic occlusion with stable (or decreased) aneurysm size on cross-sectional imaging (CT or MR) at 180 days postprocedure. Safety is defined as the patient being free of any major ipsilateral neurologic event (defined as change in NIHSS from baseline >4 points) including ipsilateral neurologic stroke or death at 180 days postprocedure.

Data Safety Monitoring Board

A data safety monitoring board will comprise 4 members not participating in the trial and will include a neuroradiologist, neurologist, neurosurgeon, and statistician. The data safety monitoring board will exercise review of the overall safety of the trial, periodically review all adverse events occurring in the trial, and make recommendations to adjustments in the study protocol, should any be considered necessary for safety or other related reasons.

Sample Size

The sample size of 316 randomized subjects was selected. Sample size was based on the noninferiority design whereby the proportion of success under the endovascular coiling arm (the active control arm) is considered to be 0.75, the noninferiority margin (Δ) is set at 0.15, the type I error is selected to be 0.025, there are 2 interim analyses for futility, a 15% inflation because of potential loss to follow-up, and 80% power.

Statistical Analyses

Statistical analyses are based on a noninferiority trial to test the hypothesis that the efficacy of flow diversion is not worse than that of endovascular coiling by more than a prespecified absolute amount δ = 15% (ie, the noninferiority margin or prespecified clinically unimportant difference) for the treatment of large and giant aneurysms. Therefore, rejection of the null hypothesis indicates that the flow diversion is not inferior to the endovascular coiling by this prespecified amount. The primary analysis will be intent-to-treat and will assess efficacy with respect to the proportion of subjects with successful outcome at 180 days postrandomization using a generalized linear model adjusting for baseline aneurysm location (intradural versus extradural), presence of intraluminal thrombus (“yes” versus “no”), aneurysm shape (saccular versus fusiform), and undergoing balloon test occlusion (“yes” versus “no”). The primary approach to handling missing primary outcome data, ie, if a subject has a missing angiogram at the 180-day visit or does not attend the 180-day clinical follow-up visit, will be to consider the subject a treatment failure for the primary effectiveness end point.

Additional potentially confounding variables (ie, sex, race, ethnicity, baseline risk factors) will be considered as covariates in secondary analyses of the primary outcome. Univariate analyses of these covariates will first be conducted to determine inclusion in the multivariate model.

As specified in the objectives, if noninferiority is demonstrated, then superiority of the safety end point will be assessed. Safety outcomes include the proportion of subjects who experience any treatment-related serious adverse events during the treatment phase and up to 180 days following completion of the treatment. The treatment-related serious adverse events will be considered along with the following:

1. Neurologic deterioration during the hospitalization phase.

2. All deaths by cause (broad categories) within 180 days of randomization.

3. Incidence of neurologic death by 180 days.

A number of secondary analyses will be conducted:

• Incidence of device or procedure related adverse events at 180 days, 1 year, and 3 years.

• Aneurysm rupture or retreatment of index aneurysm rates at 180 days, 1 year, and 3 years.

• Change in clinical functional outcome at 180 days, 1 year, and 3 years postendovascular treatment procedure, as measured by an increase in the modified Rankin Scale from baseline.

• Incidence of worsening of baseline neurologic signs/symptoms as measured by NIHSS or ophthalmologic examination related to target IA at 180 days.

• Number of inpatient hospital (and re-hospitalized) days (subgrouped >7 days) at 180 days, 1 year, and 3 years.

• Packing attenuation as measured by volumetric filling of the aneurysm if aneurysm is coiled.

• Device cost of therapy at treatment and any subsequent retreatment.

• Procedure time, as measured as the time from placement of the treating guide catheter for purposes of aneurysm treatment (not balloon test occlusion) until guide catheter removal.

Prespecified subgroup analyses will also be conducted on clinical and angiographic outcomes for the following:

• Subjects with aneurysms 10–20 mm and >2 cm.

• Intradural versus extradural location.

• Reconstructive versus deconstructive technique.

• Downstream flow-related ischemic stroke, parenchymal hemorrhage, subarachnoid hemorrhage.

• Complete aneurysm occlusion and no neurologic events at 6 months.

• IA neck size ≥4 mm versus <4 mm.

• Current/former smoker versus never smoker.

Technical success, defined as: for flow diversion, the proportion of patients in whom at least 1 attempt was made to pass the access catheter distal to the target IA in whom the final location of placed flow diverters covers the IA neck. For endovascular coiling, the proportion of patients in whom at least 1 attempt was made to pass the access catheter into the target IA fundus (for coil delivery) in whom at least 1 coil was left behind in the target IA. If the plan is for deconstructive treatment, then the parent vessel supplying the artery is occluded without residual flow.

All models will be assessed with and without covariates (age, aneurysm location, etc); this is in keeping with our randomization scheme and is not anticipated to negatively affect the power of the test.

Two protocol-specified interim analyses for futility are planned to be conducted when approximately one-third (n = 105) and two-thirds (n = 210) of the total required number of randomized subjects have been evaluated for the primary outcome. These interim analyses will use the error spending function method with O'Brien and Fleming–type stopping guidelines.^26⇓–28 The error spending function distributes the type I and II error rates across the interim monitoring points giving the flexibility of changing the intervals of monitoring while still preserving the overall type I and II error rates. The O'Brien and Fleming–type boundary is considered conservative as its boundaries make it difficult to terminate a study early on by requiring extreme early evidence of futility. It spends smaller amounts of alpha at the first look and gradually increases the spending as more information is acquired. The trial may be stopped for futility at the planned interim analyses if the test statistic crosses the respective boundaries.

Study Organization and Funding

The trial was funded in November 2012 through a collaborative sponsorship with equal participation from Codman, Microvention-Terumo, Penumbra, and Stryker. Enrollment began in March 2013 and is currently enrolling patients. The trial is international with sites in the United States, Canada, France, Italy, Spain, and Turkey. The clinical and statistical and data coordination for the trial is being conducted at the Medical University of South Carolina in Charleston, SC.