VERiTAS II REFRESHED
VERiTAS II REFRESHED
Recent prospective observational data has established that hemodynamic compromise identifies
 a high risk subgroup of patients with symptomatic intracranial atherosclerotic disease. The
 currently proposed study aims to determine if an endovascular intervention, submaximal
 balloon angioplasty, can be performed with adequate safety in this high risk subgroup of
 hemodynamically-compromised patients with intracranial atherosclerotic stenosis. The study
 will also examine as secondary aims, the effect of the intervention on hemodynamics and on
 subsequent in-territory ischemic events.
VERiTAS II REFRESHED is a prospective single-arm multi-center study to assess the safety of
 submaximal balloon angioplasty in conjunction with intensive medical management in patients
 with hemodynamically-compromised symptomatic 70-99% atherosclerotic intracranial stenosis
 (ICAS). This study builds on lines of evidence from prior prospective studies which
 established the markedly elevated risk of subsequent stroke in patients with hemodynamic
 compromise, and preliminary data from small case series which support submaximal angioplasty
 as a potentially safe option for revascularization. The primary objective of the current
 study is to determine the safety of submaximal balloon angioplasty for treatment of
 hemodynamically-compromised symptomatic ICAS. The secondary objectives are to obtain
 preliminary estimates of the risk of subsequent in-territory stroke at one year, to evaluate
 the hemodynamic effect of submaximal balloon angioplasty on distal blood flow, and to examine
 the hemodynamic durability of submaximal balloon angioplasty over follow-up.

 A total of 124 patients will be enrolled in this open-label study to receive the submaximal
 angioplasty intervention in conjunction with intensive medical management. Patients with
 stroke attributable to ICAS serve as the source population for the study, and will be
 identified as inpatients or outpatients at participating centers or their referring site.
 Patients with recently (within 30 days prior to enrollment) symptomatic 70-99% ICAS of the
 intracranial internal carotid (ICA), middle cerebral (MCA), vertebral (VA) or basilar (BA)
 artery will first be identified by a standard of care screening imaging modality (CTA, MRA,
 DSA). If the patient is eligible based on available inclusion/exclusion criteria, informed
 consent will be obtained and MRI/ quantitative magnetic resonance angiography (QMRA) will be
 performed (if not already as standard care); patients demonstrating evidence of hemodynamic
 compromise based on borderzone infarct pattern for the anterior circulation (ICA and MCA) and
 by low flow state on QMRA for the posterior circulation (VA and BA) will be enrolled. QMRA
 will be used for determination of eligibility in posterior circulation ICAS patients, but
 will be performed in both anterior and posterior circulation patients as a baseline for
 hemodynamic comparison post-procedure. The patient will then undergo catheter angiography (if
 not performed already as standard care) to confirm eligible intracranial ICAS.

 The participant will undergo submaximal angioplasty in accordance with the study protocol
 within 48 hours of angiographic confirmation, followed by SAMMPRIS regimen intensive medical
 management, including initial dual antiplatelet therapy (aspirin and Clopidogrel for 3 months
 followed by aspirin monotherapy), and targeting primary and secondary stroke risk factors.
 Assistance in achieving the risk factor goals will be provided by an INTERxVENT lifestyle
 coach, who will call the participant by phone at 1, 3, 5, 7, 9, 11 weeks, and then every 4
 weeks throughout follow-up. On a scheduled basis, INTERxVENT will send a report of the
 participants progress and goals for risk factor modification, to the participant and study
 coordinator/ study neurologist. Participants will have follow-up for a total of one year. All
 participants will have clinical visits at 1, 4, 8, and 12 months, performed by local study
 personnel not directly involved with the intervention. The study visits will include
 assessment of neurological, functional and cognitive status, as well as status of primary and
 secondary stroke risk factor control. QMRA will be performed post procedure and at 12 months;
 the follow-up QMRA results will be blinded to the local study personnel and patients. The
 main outcomes of interest are: (1) any periprocedural (within 30 day) stroke or death; (2)
 stroke in the symptomatic vessel territory; and (3) distal flow status post procedure and at
 follow-up (using QMRA). Additional measured endpoints will included functional and cognitive
 outcomes at follow-up.

 The sample size calculations have been based on a confidence interval (CI) approach aimed
 determining if the intervention can be performed with a clinically specified periprocedural
 event rate of 5% (90% CI 2,10%), in order to establish sufficient periprocedural safety of
 submaximal angioplasty to warrant further investigation in a future randomized trial. The
 sample size calculation assumes a CI approach around the stroke/death event rate at 30 days;
 for the presumed event rate of 5%, a sample size of N=117 would yield a 90% CI of (2%,10%).
 Adjusting for the inflation factor 1.02 due to a planned interim analysis and a 4% attrition
 rate for the 30 day follow-up, 124 patients are required for analysis of the primary safety
 endpoint. An interim analysis of safety is planned with a stopping rule if 30 day
 periprocedural risk exceeds 5 % (i.e. lower bound of CI of observed estimate exceeds the
 threshold). To ensure that the intervention is stopped early if it is harmful, the timing of
 the interim analysis will be flexible, to occur once 30 day follow-up has been completed on
 one third of patients (41 patients) or alternatively, when 12 events are observed, whichever
 comes first; the number of events, 12, has been specified as the minimal event number which
 would result in the lower bound of the 90% CI exceeding 5% and thus claim a >5% event rate.
 As related to study's go/no go criteria for a future phase 3 trial, our definitive no go
 parameter is proposed as the lower bound of the observed pre-specified CI exceeding the
 safety (30 day periprocedural risk) threshold of 5%. Other outcomes from the study (i.e. the
 secondary clinical and hemodynamic endpoints at 12m) would also be taken into account in
 determining whether the procedure warrants additional study in a phase 3 trial.
Inclusion Criteria:

 Participants must meet all inclusion criteria for enrollment into the study

 -  Non-severe recent stroke (within 30 days) attributed to 70-99% stenosis of
 intracranial artery (ICA, MCA, VA, BA) - may be diagnosed by MRA, CTA or DSA to
 qualify for angiogram performed as part of the study, but must be confirmed by
 catheter angiography for enrollment into the trial

 -  Hemodynamic compromise based on borderzone infarct pattern for the anterior
 circulation (ICA and MCA) and by low flow state on QMRA for the posterior circulation
 (VA and BA).

 -  Target vessel with minimal nominal diameter of 2mm

 -  Target length of stenosis <18mm

 -  Symptoms within 30 days of enrollment

 -  Age 18 and above

 -  Able to provide informed consent

 Exclusion Criteria:

 An individual who meets any of the following criteria will be excluded from study
 participation

 Neurologic:

 -  Major disabling stroke mRS >3; progressive or fluctuating deficit within 24 hours

 -  Hemorrhagic infarction (based on CT) within 14 days of enrollment

 -  Any large stroke (>5cm) to be at risk for hemorrhagic conversion

 Medical:

 -  Any neurological disease which would confound follow-up assessment

 -  Any co-morbid disease condition with <12 month life expectancy

 -  Known cardiac disease associated with elevated cardioembolic risk, specifically,
 atrial fibrillation, prosthetic valve, endocarditis, left atrial/ventricular thrombus,
 cardiomyopathy with EF<25%, cardiac myxoma

 -  Blood dyscrasias, specifically polycythemia vera, essential thrombocytosis, sickle
 cell disease

 -  Active bleeding diathesis, h/o major systemic hemorrhage within 30 days, active PUD,
 platelets<100K (severe liver impairment (AST or ALT>3 x normal, cirrhosis)

 Target lesion:

 -  Non-atherosclerotic stenosis including dissection, fibromuscular dysplasia,
 vasculitis, radiation induced vasculopathy, suspected recanalized embolus, suspected
 vasospastic process

 -  Mori C classification of stenosis(i.e. diffuse lesion, extremely angulated >90⁰,
 excessive proximal tortuosity)Previous treatment of target lesion with stent,
 angioplasty or other mechanical device

 -  Extracranial vertebral artery or carotid artery tortuosity, stenosis or occlusion
 prohibiting access to the target lesion (Extracranial disease is not exclusionary if
 does not prohibit access to target lesion)

 Participant:

 -  Unable or unwilling to undergo MRI

 -  Unable to undergo cerebral angiography

 -  Pregnancy

 -  Concurrent participation in another study which would conflict with the current study

 -  Allergy or contraindication to aspirin or Plavix

 -  Indication for warfarin or NOAC beyond enrollment (e.g. venous thrombo-embolism,
 atrial fibrillation)

 -  Thrombolytic therapy within 24 hours