IVIG with focused ultrasound to open the motor cortex blood-brain barrier in ALS

Targeting Neuroinflammation With Enhanced Delivery of Intravenous Immunoglobulin to the Motor Cortex Using Next Generation Dome Helmet Focused Ultrasound in Amyotrophic Lateral Sclerosis: A Phase I, Open Label Trial

This will test whether giving IVIG together with focused ultrasound to open the blood-brain barrier over the primary motor cortex is safe and feasible for adults with ALS.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 6 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Sunnybrook Health Sciences Centre (Academic / other)
• Drugs / interventions: cyclophosphamide, prednisone
• Locations: 1 site (Toronto, Ontario)
• Trial ID: NCT07193953 on ClinicalTrials.gov

What this trial studies

This Phase 1, single-arm, open-label multiple-ascending-dose trial will enroll six adults with ALS to examine safety, pharmacokinetics, and delivery of IVIg to the primary motor cortex. Participants are enrolled in two sequential cohorts of three, receiving either 0.4 g/kg or 0.8 g/kg IVIg divided into two doses. The second IVIg dose is combined with a single bilateral blood-brain barrier opening of the primary motor cortex using the Next Generation Dome Helmet focused ultrasound and intravenous microbubbles. Follow-up visits occur over 24 weeks to monitor safety and pharmacodynamic outcomes.

Who should consider this trial

Good fit: Ideal candidates are adults meeting the Gold Coast criteria for ALS who can consent, communicate during the procedure, tolerate lying supine or have ≥50% predicted FVC, and meet MRI and anesthesiology fitness requirements.

Not a fit: Patients with excluded MRI findings (active infection/inflammation, multiple lobar microbleeds, significant mass lesions, meningeal enhancement), severe respiratory compromise, inability to tolerate anesthesia or FUS, or those who do not meet other eligibility criteria are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, this approach could increase delivery of IVIg to the motor cortex and enable a more effective way to target motor neuron pathology in ALS.

How similar studies have performed: Focused ultrasound blood-brain barrier opening has been performed safely in small trials for other brain conditions and has supportive preclinical data, but combining BBB opening with IVIg delivery for ALS is a novel and unproven approach.

Eligibility criteria

Inclusion Criteria:

1. Diagnosed with ALS as per the Gold Coast Criteria;
2. Aged 18 years or older;
3. Capable of providing informed consent and complying with study procedures;
4. If taking Riluzole, on a stable dose for at least 4 weeks prior to Baseline;
5. If taking Edaravone, on a stable dose of one completed cycle prior to Baseline;
6. Respiratory Function Criterion:

   * Able to lie supine without BiPAP or breathing discomfort; OR
   * Forced vital capacity or slow vital capacity ≥50% of the predicted value for sex, height and age, if available
7. Able to communicate sensations during the Dome FUS procedure.
8. Qualified fit for the anesthesia by an anesthesiologist, ASA I-III.

Exclusion Criteria:

1. MRI findings:

   1. Active infection/inflammation
   2. Acute or chronic hemorrhages, specifically \> 4 lobar microbleeds, and no siderosis or macrohemorrhages
   3. Tumor/space occupying lesion causing significant mass effect
   4. Meningeal enhancement
   5. Intracranial hypotension
2. 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
3. Clips or other metallic implanted objects in the skull or the brain, except shunts
4. Significant cardiac disease or unstable hemodynamic status including:

   1. Documented myocardial infarction within six months of screening
   2. Unstable angina on medication
   3. Unstable or worsening congestive heart failure
   4. Left ventricular ejection fraction below the lower limit of normal
   5. History of a hemodynamically unstable cardiac arrhythmia
   6. Cardiac pacemaker
   7. Severe hypertension (diastolic BP \> 100 on medication)
   8. Patient has right-to-left, bidirectional, or transient right-to-left cardiac shunts
   9. QT prolongation observed on screening ECG (QTc \> 450 for men and \> 470 for women)
5. Uncontrolled hypertension (systolic \> 150 and diastolic BP \> 100 on medication)
6. Patients should not take medications known to increase risk of hemorrhage (e.g., aspirin or class I and III anticoagulants) for at least 7 days prior to treatment or lumbar puncture; patients should not take Avastin for 30 days prior to treatment
7. History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or use of anticoagulants, specifically recent thrombosis or stroke in past 3 months; abnormal coagulation profile (PLT \< 100,00/μl), PT (\> 14 sec) or PTT (\> 36 sec), and INR \> 1.3
8. No more than 1 non-strategic lacune \&lt;1.5 cm
9. Known cerebral or systemic vasculopathy
10. Significant depression and at potential risk of suicide
11. Known sensitivity/allergy to gadolinium (an alternative product may be used) and DEFINITY®.
12. Any contraindications to MRI scanning, including:

    1. Large participants not fitting comfortably into the scanner
    2. Difficulty lying supine and still for up to 3 hours in the MRI unit or claustrophobia
13. Any contraindication to lumbar puncture for collection of cerebral spinal fluid, including:

    a. Intracranial hypotension
14. Untreated, uncontrolled sleep apnea
15. Impaired renal function with estimated glomerular filtration rate \< 30 mL/min/1.73m2 or on dialysis.
16. IVIg use in the previous 6 months.
17. Live viral vaccination within the 30 days before study entry
18. Currently, or in the last 3 months participated in a clinical trial delivering an investigational product or non-approved use of a drug or device or in any other type of medical research.
19. 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, uncontrolled 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®.
20. Motor cortex atrophy deemed severe enough to limit targeting
21. Previous major allergic or anaphylactic reaction to IVIg
22. Known IgA deficiency with anti-IgA.
23. Known frontotemporal dementia;
24. Definitely or possibly pregnant (if applicable);
25. Known auto-immune condition with or without neurological manifestations (e.g., multiple sclerosis (MS), systemic lupus erythematous (SLE), Rheumatoid arthritis).
26. Current, planned or previous use of oral, intramuscular or intravenous steroid drugs (such as prednisone, prednisolone, dexamethasone, triamcinolone, methylprednisolone, oxandrolone, and others), immunosuppressant drugs (azathioprine, mycophenolate, tacrolimus, sirolimus, cyclophosphamide, and others) or NSAIDs (ibuprofen, naproxen, celecoxib, and others) in the past 30 days;
27. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the participant unsuitable for enrollment

Where this trial is running

Toronto, Ontario

• Sunnybrook Health Sciences Centre — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Study coordinator: Nir Lipsman, MD, PhD, FRCPC

Conditions Amyotrophic Lateral Sclerosis; ALS; Focused Ultrasound; Blood Brain Barrier Opening; Intravenous Immunoglobulin; Motor Neuron Disease