Blood-Brain-Barrier Opening Using Focused Ultrasound With IV Contrast Agents in Patients With Early Alzheimer's Disease (BBB-Alzheimers)

Tracking Information
First Submitted Date ICMJE	December 6, 2016
First Posted Date ICMJE	December 8, 2016
Last Update Posted Date	June 14, 2018
Study Start Date ICMJE	December 2016
Actual Primary Completion Date	December 2017 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: December 6, 2016)	Change in contrast enhancement (intensity) following BBB disruption [ Time Frame: Immediately post treatment ]; Change in contrast enhancement (intensity) following BBB disruption to pre-sonication images as a comparative ratio measured in percent as read from MR images and normalized to the contralateral hemisphere
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT02986932 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: December 6, 2016)	Change in amyloid uptake [ Time Frame: 30 days after treatments ]Change in amyloid uptake as compared to pre treatment scans in the targeted region; Adverse events [ Time Frame: 90 days ]Number of participants with treatment-related adverse events as assessed by CTCAE v4.0; MMSE - Mini Mental State Examination [ Time Frame: 30 days ]Treatment effect on patients' dementia state; ADAS-Cog - Alzheimer's Disease Assessment Scale - Cognitive Behavior subscales [ Time Frame: 30 days ]Treatment effect on patients' Alzheimer's disease symptoms; NPI - Neuropsychiatry Inventory [ Time Frame: 30 days ]Treatment effect on patients' dementia; GDS - Geriatric Depression Scale [ Time Frame: 30 days ]Treatment effect on patients' depression; ADCS-ADL - Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory [ Time Frame: 30 days ]Treatment effect on patients' activities of daily living
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Blood-Brain-Barrier Opening Using Focused Ultrasound With IV Contrast Agents in Patients With Early Alzheimer's Disease
Official Title ICMJE	A Study to Evaluate the Safety and Feasibility of Blood-Brain Barrier (BBB) Opening Using Transcranial MR-Guided Focused Ultrasound With Intravenous Ultrasound Contrast Agents in Patients With Early Alzheimer's Disease
Brief Summary	This is a prospective, non-randomized, single-arm, feasibility study to evaluate the safety and initial effectiveness of opening of the Blood-Brain Barrier with intravenous contrast agents using the ExAblate Neuro System in patients with early stage Alzheimer's Disease.
Detailed Description	This study is a prospective, single-arm, non-randomized, feasibility, phase I trial to evaluate the safety of focal BBB opening using the ExAblate® Transcranial (220 kHz) system and Definity® ultrasound contrast in 6 patients with mild Alzheimer's Disease. This phase I trial will be divided into two stages. In the first stage, patients will undergo small volume BBB opening, establishing the minimum required sonication parameters to open the BBB, as evidenced by gadolinium enhancement on T1-weighted MRI. Stage I is defined as a discrete region of approximately 9 mm x 9 mm area in the right frontal lobe. Multiple sonications will be performed starting at low energy and ramping up until the BBB is observed to open. The subjects will then be removed from the ExAblate® Neuro device and followed for safety for 30 days. If the subject experienced BBB opening without any serious adverse effects (such as brain edema), then the subject may proceed to Stage two where a larger volume (2.5-3.0 cm) will be targeted. Subjects will be followed for an additional 60 days for safety and preliminary effectiveness.
Study Type ICMJE	Interventional
Study Phase	Not Applicable
Study Design ICMJE	Intervention Model: Single Group Assignment; Intervention Model Description: Transcranial ExAblate Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Alzheimer Disease
Intervention ICMJE	Device: BBB opening; Open BBB using ExAblate focused ultrasound and (Definity®) contrast agent
Study Arms	Experimental: BBB opening; ExAblate focused ultrasound under MRI-guidance delivered through the intact human skull in conjunction with timed intravenous ultrasound contrast agents (Definity®) to temporarily and focally open the BBB.; Intervention: Device: BBB opening
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: December 6, 2016)	6
Original Estimated Enrollment ICMJE	Same as current
Actual Study Completion Date	December 2017
Actual Primary Completion Date	December 2017 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Probable AD consistent with NIA/AA criteria (McKhann, Alzheimer & Dementia 2011); Modified Hachinski Ischemia Scale (MHIS) score of <= 4.; Mini Mental State Exam (MMSE) scores 18-28; Short form Geriatric Depression Scale (GDS) score of <= 6; Has a Florbetaben PET scan consistent with the presence of amyloid pathology in the proposed target region (right frontal lobe); Able to communicate sensations during the ExAblate® MRgFUS procedure. Exclusion Criteria: MRI findings: Active infection/inflammation Acute or chronic hemorrhages, specifically > 4 lobar microbleeds, and no siderosis or macrohemorrhages Tumor/space occupying lesion Meningeal enhancement; 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; Clips or other metallic implanted objects in the skull or the brain, except shunts; other metallic objects implanted in body; Significant cardiac disease or unstable hemodynamic status including:; Uncontrolled hypertension on medication or abnormal ECG; Medications known to increase risk of hemorrhage, (e.g.: patients should be off of aspirin or another anticoagulants for at least 7 days prior to treatment) or anticoagulants (class I and III) or off Avastin for 30 days; History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or use of anticoagulants; Abnormal coagulation profile (PLT < 100,00/μl), PT (>14 sec) or PTT (>36 sec), and INR > 1.3; No more than 1 non-strategic lacune <1.5 cm; Known cerebral or systemic vasculopathy; Significant depression and at potential risk of suicide; Known sensitivity/allergy to gadolinium (an alternative product may be used), Definity or any of its components.; Any contraindications to MRI scanning such as metallic implants, claustrophibia or too large for MRI scanner; Untreated, uncontrolled sleep apnea; Impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2; Does not have a reliable caregiver in frequent contact with the patient and can accompany the patient to the clinic and treatment or be available by telephone at designated times. Participants living in retirement homes may be included. Caregiver not willing to sign the Informed Consent Form; Respiratory: chronic pulmonary disorders e.g. severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, patients with a history of drug allergies, asthma or hay fever, and multiple allergies where the benefit/risk of administering Definity® is considered unfavorable by the study physicians in relation to the product monograph for Definity.; Currently in a clinical teial involving investigational product.
Sex/Gender	Sexes Eligible for Study: All
Ages	55 Years to 85 Years (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Canada
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT02986932
Other Study ID Numbers ICMJE	AL001
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Plan to Share IPD: No
Responsible Party	InSightec
Study Sponsor ICMJE	InSightec
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Nir Lipsman, MD, PhD Sunnybrook Health Sciences Centre
PRS Account	InSightec
Verification Date	June 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP