Intravenous Immunoglobulin (IVIG) and Blood-Brain Barrier Disruption in Amyotrophic Lateral Sclerosis (ALS)

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE1

Total Enrollment

6 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-04-15

Study Completion Date

2027-05-30

Brief Summary

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The goal of this study is to evaluate the safety and feasibility of IVIg administration in conjunction with primary motor cortex BBB opening using the Next Generation Dome Helmet (NGDH) FUS in adult participants with ALS.

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Detailed Description

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This study is a prospective, single-arm, open-label, multiple-ascending dose (MAD), phase I trial to evaluate safety, feasibility, pharmacodynamics, and pharmacokinetics of enhanced delivery of IVIg 0.4 or 0.8g/kg to the primary motor cortex in 6 patients with ALS by using a single BBB opening procedure targeting the primary motor cortex in both brain hemispheres. Six participants will be enrolled in two sequential cohorts. The first cohort (n = 3) will receive 0.4g/kg of IVIg divided in two doses, while the second cohort (n = 3) will receive a 0.8g/kg of IVIg divided in two doses. In both cohorts, the second dose of IVIg will be accompanied by a single BBB opening procedure targeting the primary motor cortex in both brain hemispheres with focused ultrasound (FUS) using Next Generation Dome Helmet and intravenous microbubbles (DEFINITY®, Lantheus Medical Imaging Canada, Inc., Montreal, QC, Canada). This FUS procedure will occur during 2 weeks after the first dose administration. Follow-up visits will occur over the span of 24 weeks from the first dose.

Conditions

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Amyotrophic Lateral Sclerosis ALS

Study Design

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Allocation Method

NA

Intervention Model

SEQUENTIAL

The first cohort (n = 3) will receive 0.4g/kg of IVIg, divided into two 0.2g/kg doses. After a preliminary safety and tolerability assessment of the first cohort, patients will be enrolled to the second cohort (n = 3). It will follow the same design but with 0.8g/kg divided into two 0.4g/kg doses.

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Intravenous Immunoglobulin Administration using Focused Ultrasound

ALS patients will be assigned to receive Intravenous Immunoglobulin (IVIg) and DEFINITY® microbubbles. The first three enrolled patients will participate in the first cohort, receiving 0.4g/kg divided in two doses. After a preliminary safety assessment of the first cohort, the next three successfully screened patients will be enrolled in the second cohort, receiving 0.8g/kg divided in two doses. The second IVIg dose in each cohort will be administered in combination with Next Generation Dome Helmet (NGDH) focused ultrasound (FUS) to transiently open the blood-brain barrier and enhance IVIg delivery to the primary motor cortex.

Group Type EXPERIMENTAL

Next Generation Dome Helmet Focused Ultrasound

Intervention Type DEVICE

Two doses of IVIg will be administered 2 weeks apart. The first dose at Week 0 will be a standalone administration. The second dose at Week 2 will be combined with Next Generation Dome Helmet (NGDH) Focused Ultrasound (FUS) blood brain barrier (BBB) opening.

Intravenous immunoglobulin (IVIG), 10% solution for infusion

Intervention Type DRUG

Two doses of IVIg will be administered 2 weeks apart. The first dose at Week 0 will be a standalone administration. The second dose at Week 2 will be combined with Next Generation Dome Helmet (NGDH) Focused Ultrasound (FUS) blood brain barrier (BBB) opening. Cohort I will receive 0.2g/kg of IVIg at each dose. Cohort II will receive 0.4g/kg of IVIg at each dose.

Privigen® IVIg comes in vials containing 10% active ingredient. It is supplied in 2.5 g (25 mL bottle), 5 g (50 mL bottle), 10 g (100 mL bottle), 20 g (200 mL bottle) or 40 g (400 mL bottle). The IVIg dose will be determined based on the patient's ideal body weight.

Definity® Vial for (Perflutren Lipid Microsphere) Injectable Suspension

Intervention Type DRUG

DEFINITY® Perflutren Injectable Microbubbles is an ultrasound contrast imaging agent that will be used for blood brain barrier opening during focused ultrasound. These microbubbles will be injected during the focused ultrasound procedure on the day of the second IVIg dose.

Interventions

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Next Generation Dome Helmet Focused Ultrasound

Two doses of IVIg will be administered 2 weeks apart. The first dose at Week 0 will be a standalone administration. The second dose at Week 2 will be combined with Next Generation Dome Helmet (NGDH) Focused Ultrasound (FUS) blood brain barrier (BBB) opening.

Intervention Type DEVICE

Intravenous immunoglobulin (IVIG), 10% solution for infusion

Two doses of IVIg will be administered 2 weeks apart. The first dose at Week 0 will be a standalone administration. The second dose at Week 2 will be combined with Next Generation Dome Helmet (NGDH) Focused Ultrasound (FUS) blood brain barrier (BBB) opening. Cohort I will receive 0.2g/kg of IVIg at each dose. Cohort II will receive 0.4g/kg of IVIg at each dose.

Privigen® IVIg comes in vials containing 10% active ingredient. It is supplied in 2.5 g (25 mL bottle), 5 g (50 mL bottle), 10 g (100 mL bottle), 20 g (200 mL bottle) or 40 g (400 mL bottle). The IVIg dose will be determined based on the patient's ideal body weight.

Intervention Type DRUG

Definity® Vial for (Perflutren Lipid Microsphere) Injectable Suspension

DEFINITY® Perflutren Injectable Microbubbles is an ultrasound contrast imaging agent that will be used for blood brain barrier opening during focused ultrasound. These microbubbles will be injected during the focused ultrasound procedure on the day of the second IVIg dose.

Intervention Type DRUG

Eligibility Criteria

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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 \<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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Dr. Nir Lipsman

Chief of Hurvitz Brain Sciences Program, Director of Harquail Centre for Neuromodulation, Director of Neurosurgery Residency Program, Principal Investigator, Associate Professor

Responsibility Role PRINCIPAL_INVESTIGATOR