Therapeutic Approach of Repeated Transient Blood-brain Barrier Opening in Amyotrophic Lateral Sclerosis. A One-arm, Single-center, Proof-of-concept Study (Son-ALS)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Phase 1 : Adverse events frequency and severity during study to assess the safety of ultrasound induced BBB opening in the upper motor neuron area and adjacent supplementary motor area
研究概览
简要总结
This is proof-of-concept, single-arm, single-center study to assess the safety and explore the efficacy of repeated US transient disruptions of the blood-brain barrier (BBB) in Amyotrophic Lateral Sclerosis (ALS).
Phase 1:
The primary objective is to assess the safety of ultrasound induced BBB opening in the upper motor neuron area and adjacent supplementary motor area in adult patients with ALS, as assessed by adverse events frequency and severity during study (incidence of AE summarized by system organ class and/or preferred term and severity) based on the Common Terminology Criteria for Adverse Events, version 5.0 A run-in period of 12 weeks between inclusion and baseline will take place for each patient in order to evaluate precisely disease progression rate, disease severity and to collect concomitant medication. After this run-in period, the patient will be implanted with the SC4 device (baseline visit). The first sonication session will be performed two weeks after implantation. A total of 9 sonications, with no concomitant drug administration, will be performed over a period of 24 weeks.
Phase 2a:
Based on the safety outcome of the Phase 1, an expansion cohort will open to assess the first signal of efficacy of the US transient disruptions of the BBB in ALS. The primary objective will be to assess the first signal of efficacy of the procedure on disease progression over 26 weeks evaluated by the change from baseline to week 26 of neurofilament light (NfL) levels in blood.The Phase 2a will continuously include 11 additional patients. Patients will be treated according to the same schedule as in phase 1
详细描述
The blood-brain barrier (BBB) significantly limits drug delivery to the central nervous system and contributes to the difficulty of developing effective treatments for Amyotrophic Lateral Sclerosis (ALS). Low intensity pulsed ultrasound can be used to transiently disrupt the BBB without tissue damage, to enhance drug penetration. Ultrasound-induced BBB disruption can also modulate the immune response in the central nervous system and may thus also be therapeutic by itself in ALS by stimulating innate and cellular immune responses.
This is proof-of-concept, single-arm, single-center, phase 1/2a study to assess the safety and explore the efficacy of repeated US transient disruptions of the BBB in ALS.
The primary objective of the phase 1 study is to assess the safety of ultrasound induced BBB opening in the upper motor neuron area and adjacent supplementary motor area in adult patients with ALS. Based on the safety outcome of the phase 1, an expansion cohort will open to assess the first signal of efficacy of the US transient disruptions of the blood-brain barrier in ALS. The inclusion visit will take place 12 weeks before the baseline visit. Clinical evaluation of motor function, pulmonary function tests and brain MRI (for future device positioning and safety comparison with post explantation MRI) will be performed, and implantation will be planned after a run-in period of 12 weeks.
The baseline visit corresponds to the implantation of SC4 device and the patient will be hospitalized in the Neurosurgery department. Clinical evaluation (ALSFRS-R, manual muscle testing), pulmonary function tests and ALSAQ-5 quality of life evaluation will be performed before implantation as well as blood samplings for serum NfL and baseline immune status. The implantation will be performed under local anesthesia.
After 2 weeks, the first ultrasound session visit will be performed in day care hospital in the Neurosurgery department. The connection between the implant and the external generator will be made using a transdermal needle.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-80 years,
- •Able and willing to give signed and informed consent
- •Confirmed diagnosis of ALS using the Gold Coast criteria with involvement of both upper and lower motor neurons in at least one body region, i.e. patients classified as "definite", "probable", "probable laboratory supported" or "possible" ALS using the El Escorial categories (patients with only lower motor neuron involvement will not be included)
- •Disease duration <= 36 months,
- •Mild functional impairment (ALSFRS-R ≥30),
- •Change in ALSFRS-R score between 0.35 points and 1.1 points per month (both inclusive) in the period from onset of first symptoms to the Screening visit,
- •Slow Vital capacity >= 70% of normal,
- •If taking riluzole, patient on stable dose for over 30 days prior to study entry,
- •Able and willing to follow trial procedures including site travels and visit requirements
排除标准
- •Patients with an uncontrolled intercurrent illness or any pre-existing comorbidities that in the Investigator's opinion may prevent the implantation of the device or may impair the ability of the patient to receive treatment with SonoCloud or may be cofounding for evaluation of the clinical trial
- •Cardiac pacemaker (contraindication to MRI)
- •Allergy to any drug used in the study (Gadolinium, Xylocain, Cloxacilline, EMLA, echographic contrast agent microbubbles: SonoVue®)
- •Severe or instable chronic or acute disease or any life-threatening condition
- •Other significant neurological or psychiatric disease in addition to ALS, including history of uncontrolled seizures
- •Treatment with edaravone, tofersen or with another investigational drug or biological agent within 1 month or 5 half-lives of study agent, whichever is longer, before screening
- •Invasive or non-invasive mechanical ventilation use
- •Gastrostomy or nasogastric tube use
- •Known right-to-left shunts,
- •Known severe pulmonary hypertension (pulmonary artery pressure >90 mmHg), uncontrolled systemic hypertension
- •Known respiratory distress syndrome
- •Women of child-bearing potential or sexually active man, without contraception
- •Pregnant or breast-feeding woman
- •History or positive test result at screening for HIV, current hepatitis C infection (defined as positive HCV antibody and detectable HCV RNA) or current hepatitis B infection (defined as positive for HBsAg and/or total anti-HBc). Participants with positive HCV antibody and undetectable HCV RNA are eligible to participate in the study. Participants with immunity to hepatitis B from previous natural infection (defined as negative HbsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HbsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
- •Patient not affiliated or beneficiary of a social security category
研究组 & 干预措施
Sonications
Repeated US transient disruptions of the blood-brain barrier
干预措施: SonoCloud-4 (SC4) device (Device)
结局指标
主要结局
Phase 1 : Adverse events frequency and severity during study to assess the safety of ultrasound induced BBB opening in the upper motor neuron area and adjacent supplementary motor area
时间窗: from inclusion up to 50 weeks
incidence of AE summarized by system organ class and/or preferred term and severity based on the Common Terminology Criteria for Adverse Events, version 5.0
Phase 2a : Neurofilament light (NfL) levels in blood to assess the first signal of efficacy of the procedure on disease progression
时间窗: from baseline to 26 weeks
Change from baseline to week 26 of neurofilament light (NfL) levels in blood
次要结局
- ALSFRS-R score (ALS functional rating scale (revised),(from baseline to 26 weeks)
- ALSFRS-R slope(from baseline to 26 weeks)
- ALSFRS-R score(from baseline to weeks 8)
- Overall Survival (OS)(from baseline to 12 months after the last inclusion)
- QOL (Quality of Life)(26 weeks)
- ALSFRS-R score (Amyotrophic Lateral Sclerosis Functional Rating Scale)(from baseline to weeks 20)
- Muscle strength(from baseline to 26 weeks)
- Neurofilament light (NfL)(from baseline to 26 weeks)
- Neurofilament light (Nfl)(From baseline to week 2)
- protein S100β, Aquaporin-4 and NSE(From baseline to week 2)
- gadolinium enhancement on MRI(From baseline to week 2)