Effect of DIRECT Transfer to ANGIOsuite on Functional Outcome in Severe Acute Stroke

Methods:

Design: The DIRECT ANGIO trial is a French academic, investigator-initiated, multicenter, controlled, open-label, blinded endpoint, two-arm randomized, clinical trial to compare the effectiveness and safety of direct angio-suite admission versus the standard radiological or emergency departement-based management in ≤75 year-old patients with suspected proximal arterial occlusion lesion. As of March 2020, 9 comprehensive stroke centres (Besançon, Bordeaux, Colmar, Limoges, Montpellier, Nancy, Reims, Foch Hospital, Rothschild foundation) have agreed to participate.

Patient population: As of the phone call from the emergency rescue service, the neurologist/the emergency medical doctor will check inclusion and exclusion criteria and then randomize the patient during the travel to the hospital.

Inclusion criteria: All consecutive patients with the following features are enrolled, under the condition of immediate availability of the angio-suite and the medical team:

- aged 18 to ≤75 years,

- strongly suspected of having an acute and severe neurological deficit related to acute large-vessel occlusion of the anterior circulation (hemiparesis or hemiplegia with at least one sign of cortical damage : aphasia, hemianopsia, hemi-neglect, deviation of the head and eyes),

- who can be admitted to hospital within an anticipated 5 hours after symptom onset,

According to the French laws, oral informed consent will be sought via telephone conversations from patient if their level of consciousness is sufficient or from their relatives. Written informed consent will be then given at hospital. In case of inability to consent and absence of the relatives, informed consent to follow will be obtained.

Exclusion criteria are detailed below.

Randomization: After inclusion and before hospital arrival, i.e. during the transfer to the hospital, patients are randomized in the two treatment arms using a web-based centralized system with a 1:1 ratio to either direct angio-suite management or standard management. To deal with open-label, 3-month functional outcome is gathered with blinding to randomization arm.

Treatment and Intervention

Intervention Arm: Upon arrival in angio-suite and after neurological examination with scoring National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS), and performing blood sampling, electrocardiogram and weight estimation, patient undergoes rotational Cone Beam CT (CBCT) in order to confirm ischemic stroke and CBCT-angiography in order to confirm proximal arterial occlusion lesion. Mechanical thrombectomy is then performed as well as intravenous thrombolysis when contraindications are excluded.

It should be noted that in the absence of proximal or distal intracranial arterial occlusion, the patient will be redirected to standard management as in the control arm. They will thus benefit from cerebral MRI/CT-scan and the treatment strategy will then be determined.

Control Arm: Arrival is in the MRI/CT-scan room or in the emergency department. Directly after neurological examination and blood sample, patient undergoes imaging. If required, patient undergoes intravenous thrombolysis directly in the MRI/CT-scan room or after transfer in the stroke unit or in the emergency service, according to the practices of the centres involved.

In a second step, the patient is admitted in the angio-suite if mechanical thrombectomy indicated. The transfer to angio-suite will be carried out as soon as possible.

All patients data will be recorded in an electronic case report form (e-CRF) and imagings will be recorded in a centralized database, located in the Clinical Investigation Centre-Technological Innovation of Nancy, in order to a centralized radiological reading by the Imaging Core Lab.

Clinical assessment

Clinical evaluation is conducted early, as soon as the first telephone contact with the emergency rescue service or the fire brigade, by the neurologist at the participating centre who confirms that the patients meet the inclusion criteria.

Clinical assessment includes then demographics and collection of routine clinical information (comorbidities, symptoms, vital constants), allergy contraindications. Neurological deficit will be assessed using the NIHSS score and pre-stroke disability with mRS by a neurologist at hospital admission.

At 3 months (±15 days) and 12 months (±1 month), the mRS score will be centralized gathered by a trained clinical research nurse blinded to randomization group via a telephone conversation. The 12-month outcome assessment comprises medical ongoing treatment, vital status, serious adverse effect and EQ-5D questionnaire.

Care workflow time will record all the delays between each strategy time (onset-to-admission in angio-suite/radiology department time; onset-to-intravenous thrombolysis, onset-to-groin puncture, onset-to-reperfusion times).

Imaging protocol Baseline imaging characteristics in the standard management group is either magnetic resonance imaging with 3D-Time of Flight (TOF) sequence or CT-scan with intracranial angiography and CT-perfusion sequence. In the angio-suite group, rotational CBCT and CBCT-angiography will be performed.

The imaging protocol in angio-suite will be harmonized between the centres and the quality of the images evaluated before the study is implemented.

Furthermore, if mechanical thrombectomy is indicated, angiographic perfusion will be assessed with the modified Treatment In Cerebral Ischemia (mTICI) score on initial and final angiograms and collateral status with the Grading Collateral System (GCS) score on initial angiogram, in the two groups.

Primary Outcomes The primary outcome is the rate of patients with 3-month functional independence defined as modified Rankin Scale score ≤2 at 3 months (±15 days), irrespective of the pathology that actually led to the hospitalisation and of the treatment actually received. It will be centralized gathered via telephone conversations with patients and their relatives by a certified clinical research nurse with blinding to the randomized group.

Secondary Outcomes

Secondary feasibility outcomes will include

- the rate of confirmed large-vessel stroke in the intervention and the control groups,

- the rate of proximal intracranial occlusion of the anterior circulation in the intervention group,

- the hospital admission-to-imaging time / the admission-to-thrombolysis time / the admission-to-puncture time / the admission-to-reperfusion time,

- the imaging-to-puncture time / the imaging-to-reperfusion time,

- the puncture-to-reperfusion time.

Secondary Effectiveness outcomes will include :

- the quality of final perfusion according to the mTICI score: percentage of patients with reperfusion defined by mTICI 0, 1, 2a, 2b, 2c, and 3 (modified Treatment In Cerebral Infarction) at the end of thrombectomy,

- the rate of complications per procedure: embolus in new territory, arterial perforation, arterial dissection

- the 24-hour (±6 hours) clinical improvement staged with the NIHSS score, the NIHSS at 5-7 days (or at hospital discharge if within 5 days),

- the blinded 12-month (±1 month) functional outcome valued by the mRS score,

- the rate of cerebral hemorrhage at admission,

- the rate of patients without proximal intracranial arterial occlusion,

- the rate of conversion to the standard management

Secondary safety outcomes will comprise:

- the rate of 24-hour asymptomatic and symptomatic intracerebral haemorrhagic transformation as defined by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST),

- the rate of overall mortality (mRS score 6) at 3-month (±15 days) and at 12 months (±1 month),

- the inhospital rate of neurosurgical procedure (malignant stroke or large intracerebral hemorrhage with mass effect).

- the rate of stroke (ischemic or hemorrhagic), of stroke unrelated to large-vessel occlusion,

- the rate of patients treated by intravenous thrombolysis alone and who required additional imaging (MRI or CT-scan),

- the rate of stroke mimics (tumour, epilepsy).

Medico-economic analyses will assess the avoided health care costs in an health insurance perspective and provide a cost-utility evaluation using the Health-Related Quality of Life Questionnaire (EQ-5D-5L) at 12-month (±1 month) from inclusion. Health costs will be collected from a national database (the National Institute of Health Data) using a matching method.

Data Monitoring Body: To ensure that appropriate ethical consideration is given to the welfare of the patients enrolled in the study, a DSMB was formed. The members of the DSMB are not participants of the DIRECT ANGIO consortium and not involved in the clinical trial. The DSMB is composed by one neuroradiologist, one pharmacovigilance specialist and one methodologist, who are not participating in the study and are not affiliated with the sponsor.

In addition, one interim analysis is planned once 50% of patients have been included, for the study to be stopped early owing either to compelling evidence of efficacy (using a pre-specified Haybittle-Peto efficacy boundary with an alpha level of 0.001) or of futility.

Sample Size Estimates:

The type I error is specified at 0.05 with a power of 80%. Assuming 30% of patients randomized in the control arm achieve 3-month mRS score ≤2 and an absolute difference of 20% between the two arms, we will need a sample size of 93 patients per group for a two-sided test. To deal with 10% drop-out, we will include a total of 208 patients.

Statistical Analyses:

Demographic and baseline clinical-radiological characteristics will be provided in the entire inclusion cohort. Descriptive statistics will include drop-out rate for each covariates and use chi-squared, Fisher's exact, Student or Mann-Whitney test when appropriate.

Comparisons between two randomized arms for the primary outcome will be made in the intention-to-treat and in the per-protocol sets with a logistic regression adjusted on the center. Odds ratio (OR) and its 95% confidence interval (CI) for dichotomous primary outcome will be reported.

The secondary efficacy and safety outcomes will be assessed with chi-square tests for categorical variables (eg, overall mortality and serious adverse events) and Student's t test for continuous variables (eg, mean 24-hour NIHSS).

In addition, one interim analysis is planned once 50% of patients have been included, for the study to be stopped early owing either to compelling evidence of efficacy (using a pre-specified Haybittle-Peto efficacy boundary with an alpha level of 0.001) or of futility.

Furthermore, the medico-economic analysis will take into account disability costs and health costs avoided with the interventional strategy. A cost-utility analysis will be also performed with health-related quality of life estimated with EQ-5D-5L questionnaire.

The study protocol was approved by the National Commission for Informatics and Liberties (CNIL), the Comité de Protection des Personnes (CPP).