Safety and Effectiveness of Blood-Brain Barrier Disruption (BBBD) in Subjects With Suspected Infiltrating Glioma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and effectiveness of using the Exablate Type 2 system using microbubble resonators (Exablate Test Arm) to disrupt the Blood-Brain Barrier for the purpose of temporarily transforming, and thereby 'marking', regions of infiltrating gliomas prior to planned surgical resection, for the purpose of improving tumor visualization during the surgery to achieve a greater proportion of subjects who receive a Gross Total Resection (GTR) per plan compared to those not undergoing a BBBD procedure prior to resection (Control Arm).

Detailed Description
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After being informed about the study and potential risks, all patients giving written informed consent will undergo screening to determine eligibility for study entry. Patients who meet the eligibility requirements will be randomized in a 2:1 ratio to Exablate Test Arm and to Control Arm, respectively. The following assessments will occur: Pre-surgical planning and Post-surgical visit MRI exams with and without contrast will be collected for evaluation by the study core lab; Any return to surgery for additional resection will be captured All subjects will be seen at  Week 2, and  4-Weeks post resection for physical and neurological exams and to assess for complications or adverse events. These visits should coincide with standard (Neuro-oncology) care following resection. Long-term outcomes will be collected during standard of care Neuro-oncology care follow-up visits for up to 2 years post resection; standard of care MRIs and RANO assessments will be collected.

Official Title
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A Pivotal Study to Evaluate the Safety and Effectiveness of Exablate Model 4000 Using Microbubble Resonators to Temporarily Mediate Blood-Brain Barrier Disruption (BBBD) in Subjects With Suspected Infiltrating Glioma

Conditions
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Glioma

Intervention / Treatment
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* Device: Exablate BBBD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female between 21-85 years of age who are able and willing to give informed consent Subjects with suspected Grade II, III or IV infiltrating glioma (IG) on pre-operative brain imaging scans who have a non-enhancing component and are planned for surgical resection. Karnofsky Performance Score 70-100 Able to communicate sensations during the Exablate BBBD procedure Exclusion Criteria: Tumor originating from the deep midline, thalamus, midbrain, cerebellum or brainstem. Multifocal tumors MRI or clinical findings of: Active or chronic infection(s) or inflammatory processes Acute or chronic hemorrhages, specifically any lobar microbleeds, and no siderosis, amyloid angiopathy, or macro-hemorrhages Intracranial thrombosis, vascular malformation, cerebral aneurysm or vasculitis More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp MR non-compatible metallic implants in the skull or the brain or the presence of unknown MR unsafe devices Significant cardiac disease or unstable hemodynamic status Documented myocardial infarction within six months of enrollment Unstable angina on medication Unstable or worsening congestive heart failure Left ventricular ejection fraction below the lower limit of normal History of a hemodynamically unstable cardiac arrhythmia Cardiac pacemaker Patient has right-to-left, bidirectional, or transient right-to-left cardiac shunts Subjects with relative contraindications to perflutren including subjects with a family or personal history of QT prolongation or taking concomitant medications known to cause QTc prolongation, Perflutren sensitivity or allergy ii. QT prolongation observed on screening ECG (QTc > 450 for men and >470 for women) Uncontrolled hypertension (systolic > 180 and diastolic BP > 120 on medication) Unable to discontinue use of anti-coagulant/antiplatelet therapy as per local standard. History of a liver disease, bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or evidence of increased risk of bleeding Abnormal coagulation profile (Platelets < 80,000), PT (>14) or PTT (>36), and INR > 1.3. Large lacunar lesions that cannot be navigated around Known cerebral or systemic vasculopathy Significant depression and at potential risk of suicide Known sensitivity/allergy to gadolinium, or other intravascular contrast agents Active seizures despite medication treatment (defined as >1 seizure per week) which could be worsened by disruption of the blood brain barrier History of anaphylactic shock Active drug or alcohol disorder which have a higher risk for seizures, infection and/or poor executive functioning Positive HIV status, which can lead to increased entry of HIV into the brain parenchyma leading to HIV encephalitis Potential blood-borne infections which can lead to increased entry to brain parenchyma leading to meningitis or brain abscess Any contraindications to MRI scanning, Impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2 Severe Respiratory Illness Currently in a clinical trial involving an investigational product or non-approved use of a drug or device Pregnancy or Lactation

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Exablate Test Arm<br>Subjects will undergo ExAblate BBBD prior to their standard of care tumor removal | Device: Exablate BBBD<br>* Blood brain barrier disruption using ExAblate Type 2 device using microbubble resonators<br>|
| No Intervention: Control Test Arm<br>Subjects will undergo their standard of care tumor removal | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall safety of the Exablate BBBD procedure itself as measured through the collection of adverse events | Safety of the Exablate BBBD procedure will be evaluated by patient examination and post-procedure MRI exams assessing changes in the treated region. Adverse events will be reported by the Investigator and monitored in both treatment arms. | Approximately 2 months | 
| Effectiveness of BBBD as determined by the proportion of subjects in whom a GTR is acheived | The proportion of subjects in whom a gross total resection (actual versus planned) is achieved as measured on post-operative imaging compared to pre-resection imaging | MRI 72 hours post resection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmation of accuracy of Exablate BBBD targeting | Confirmation that new BBBD by contrast enhancement in a previously non-enhancing area overlies the intended target for BBBD. (ExAblate arm only) | MRI immediately after the ExAblate procedure | 
| Return Rate for Second Surgery for Completion of Resection | Comparison of the Return Rate between the two treatment arms. | Approximately 2 months |