Clinical trial: Blood-Brain Barrier Opening Using MR-Guided Focused Ultrasound in Patients With Amyotrophic Lateral Sclerosis (NCT03321487)

Eligibility criteria:
Inclusion Criteria:

          1. Diagnosed with laboratory supported probable, clinically probable or definite ALS
             according to the World Federation of Neurology Revised El Escorial criteria (Brooks et
             al. 2000).

          2. Right-hand dominant male or female aged 18 years or older.

          3. Capable of providing informed consent and complying with study procedures, including
             tolerability in the supine position and MRI examination without significant
             claustrophobia.

          4. If taking riluzole, on a stable dose for at least 30 days prior to Screening Visit.

          5. Slow Vital Capacity equal to or more than 50% predicted value for gender, height and
             age in the 30 days prior to the Screening Visit and able to lie supine without BiPAP.

          6. Severe left arm weakness and functional impairment, defined as Medical Research
             Council muscle strength score equals 3 or less in the index finger abduction and thumb
             abduction on the left side; OR severe left leg weakness and functional impairment,
             defined as Medical Research Council muscle strength score equals 3 or less at the hip
             flexors and ankle dorsiflexors on the left side.

          7. Able to communicate during the ExAblate® MRI-guided FUS procedure.

        Exclusion Criteria:

          1. Unable to complete high-density CT and MRI studies of the head at the Screening Visit
             or any other MRI contraindication, such as:

               -  Large body habitus and not fitting comfortably into the scanner

               -  Difficulty lying supine and still for up to 3 hours in the MRI unit or
                  significant claustrophobia

          2. MRI findings:

               -  Active infection/inflammation

               -  Acute or chronic brain hemorrhages, specifically lobar or subcortical
                  microbleeds, siderosis or macrohemorrhages

               -  Tumor/space occupying lesion

               -  Meningeal enhancement

          3. 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.

          4. Clips or other metallic implanted objects in the skull or the brain, except shunts.

          5. Significant cardiac disease or unstable hemodynamic status including:

               -  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 or phrenic pacemaker

               -  Known right-to-left, bidirectional, or transient right-to-left cardiac shunt

               -  Patients 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,

               -  QT prolongation observed on screening ECG (QTc > 450 for men and >470 for women)

          6. Uncontrolled hypertension (systolic > 150 or diastolic BP > 100 on medication).

          7. On medications that increase the bleeding risk, specifically: a) aspirin or another
             antiplatelet medication (clopidogrel, prasugrel, ticlopidine, abciximab) for the last
             7 days prior to treatment; b) oral, subcutaneous or intravenous anticoagulant
             medications, such as oral vitamin K inhibitors for the last 7 days, non-vitamin K
             inhibitor oral anticoagulant (dabigatran, apixaban, rivaroxaban) for the last 72
             hours, and intravenous or subcutaneous heparin-derived compounds for the last 48
             hours.

          8. History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage.

          9. Known frontotemporal dementia.

         10. Abnormal coagulation profile, specifically: platelet <100,000/μl, Prothrombin Time >14
             seconds, activated partial thromboplastin time (aPTT) >36 seconds, and INR > 1.3.

         11. Known cerebral or systemic vasculopathy, specifically cerebral amyloid angiopathy or
             systemic or central nervous system vasculitis.

         12. Known auto-immune condition with or without neurological manifestations (e.g.,
             multiple sclerosis (MS), systemic lupus erythematous (SLE), Rheumatoid arthritis).

         13. Current or planned use of oral, intramuscular or intravenous steroid drugs (such as
             prednisone, prednisolone, dexamethasone, triamcinolone, methylprednisolone,
             oxandrolone, and others) or immunosuppressant drugs (azathioprine, mycophenolate,
             tacrolimus, sirolimus, cyclophosphamide, and others) for more than 7 days.

         14. Known sensitivity/allergy to gadolinium (an alternative product may be used),
             DEFINITY® contrast or any of its components.

         15. Untreated, uncontrolled sleep apnea.

         16. Impaired renal function with cystatin C-based estimated glomerular filtration rate <30
             mL/min/1.73m2 and acute renal injury.

         17. Currently in a clinical trial involving an investigational product or non-approved use
             of a drug or device.

         18. Known respiratory diseases, specifically: chronic pulmonary disorders e.g.,
             severe/uncontrolled COPD, pulmonary vasculitis, or other causes of reduced pulmonary
             vascular cross-sectional area, asthma or hay fever.

         19. Patients with a history of drug allergies or multiple allergies where the benefit/risk
             of administering DEFINITY® is considered unfavorable by the study physicians in
             relation to the product monograph for DEFINITY®.

         20. Unqualified fit for the anesthesia by an anesthesiologist assessment, ASA I-III.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.


Patient description (medical language): A 47-year-old man comes to the clinic for the follow up of his neuromuscular disease. He experienced gradual, progressive weakness of the left upper extremity over the last year.  Over the last few months, he has also noticed weakness in the right upper extremity.  BP is 120/75, PR is 80 and temperature is 37 C. Reflexes are brisk in the upper extremities, and the plantar responses are extensor.  Mild gait ataxia is present. The patient is under treatment of Riluzole 50 mg BID with the diagnosis of ALS.

Patient description (patient's own words): I've been suffering from a neuromuscular disease for a while now, and I went to my doctor's office. I'm now a 47-year-old man and over the past year I experienced a progressive and gradual weakness of my left upper extremity, and over the past month, I also noticed a weakness over my right upper extremity. My heart rate was 120/75, and my  PR was 80 with 37°C for temperature. My reflexes are not good in my upper extremities, and I have trouble with my balance. I'm also under Exservan 50 mg for my sclerosis.

Does the patient match the trial criteria? Entailment