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
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Safety of IVIg in patients with ALS
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosed with ALS as per the Gold Coast Criteria;
- •Aged 18 years or older;
- •Capable of providing informed consent and complying with study procedures;
- •If taking Riluzole, on a stable dose for at least 4 weeks prior to Baseline;
- •If taking Edaravone, on a stable dose of one completed cycle prior to Baseline;
- •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
- •Able to communicate sensations during the Dome FUS procedure.
- •Qualified fit for the anesthesia by an anesthesiologist, ASA I-III.
排除标准
- •MRI findings:
- •Active infection/inflammation
- •Acute or chronic hemorrhages, specifically > 4 lobar microbleeds, and no siderosis or macrohemorrhages
- •Tumor/space occupying lesion causing significant mass effect
- •Meningeal enhancement
- •Intracranial hypotension
- •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
- •Significant cardiac disease or unstable hemodynamic status including:
- •Documented myocardial infarction within six months of screening
- •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
- •Severe hypertension (diastolic BP > 100 on medication)
- •Patient has right-to-left, bidirectional, or transient right-to-left cardiac shunts
- •QT prolongation observed on screening ECG (QTc > 450 for men and > 470 for women)
- •Uncontrolled hypertension (systolic > 150 and diastolic BP > 100 on medication)
- •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
- •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
- •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) and DEFINITY®.
- •Any contraindications to MRI scanning, including:
- •Large participants not fitting comfortably into the scanner
- •Difficulty lying supine and still for up to 3 hours in the MRI unit or claustrophobia
- •Any contraindication to lumbar puncture for collection of cerebral spinal fluid, including:
- •a. Intracranial hypotension
- •Untreated, uncontrolled sleep apnea
- •Impaired renal function with estimated glomerular filtration rate < 30 mL/min/1.73m2 or on dialysis.
- •IVIg use in the previous 6 months.
- •Live viral vaccination within the 30 days before study entry
- •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.
- •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®.
- •Motor cortex atrophy deemed severe enough to limit targeting
- •Previous major allergic or anaphylactic reaction to IVIg
- •Known IgA deficiency with anti-IgA.
- •Known frontotemporal dementia;
- •Definitely or possibly pregnant (if applicable);
- •Known auto-immune condition with or without neurological manifestations (e.g., multiple sclerosis (MS), systemic lupus erythematous (SLE), Rheumatoid arthritis).
- •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;
- •Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the participant unsuitable for enrollment
研究组 & 干预措施
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.
干预措施: Next Generation Dome Helmet Focused Ultrasound (Device)
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.
干预措施: Intravenous immunoglobulin (IVIG), 10% solution for infusion (Drug)
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.
干预措施: Definity® Vial for (Perflutren Lipid Microsphere) Injectable Suspension (Drug)
结局指标
主要结局
Safety of IVIg in patients with ALS
时间窗: During and after IVIg administration at Week 0 and Week 2 Day 1 until Week 24.
This will be assessed up through the incidence of drug-related adverse events, serious adverse events, and discontinuations due to adverse events after Intravenous Immunoglobulin (IVIg) administration.
Safety of DEFINITY® microbubbles
时间窗: During and after DEFINITY® administration at Week 2 Day 1 until Week 24.
This will be assessed up through the incidence of drug-related adverse events, serious adverse events, and discontinuations due to adverse events after DEFINITY® infusion during focused ultrasound (FUS) blood brain barrier (BBB) opening.
Feasibility of FUS BBB opening in the motor cortex
时间窗: During and after Week 2 Day 1 FUS BBB opening until Week 24.
This will be measured as detectable gadolinium enhancement at the arm, leg and bulbar regions of the motor cortex bilaterally following FUS with posterior normalization.
Safety of FUS BBB opening in the motor cortex
时间窗: From up to 30 days before Week 0 to Week 24.
Incidence of BBB opening-related and FUS-related adverse events, serious adverse events, incidence of asymptomatic or symptomatic radiologic complication, such as evidence of bleeding or swelling after FUS, incidence of electrographic complication, such as epileptiform discharges on EEG, or accelerated ALS disease progression, defined as ≥ 6-point decline in the ALSFRS-R scores from Baseline to week 8.
次要结局
- Neurofilament light chain (NfL) levels in blood plasma and cerebrospinal fluid(From up to 30 days before Week 0 to Week 24.)
- Inflammatory markers in blood and cerebrospinal fluid(From up to 30 days before Week 0 to Week 24.)
研究者
Dr. Nir Lipsman
Chief of Hurvitz Brain Sciences Program, Director of Harquail Centre for Neuromodulation, Director of Neurosurgery Residency Program, Principal Investigator, Associate Professor
Sunnybrook Health Sciences Centre