Therapeutic Approach of Repeated Transient Blood-brain Barrier Opening in Amyotrophic Lateral Sclerosis.

Therapeutic Approach of Repeated Transient Blood-brain Barrier Opening in Amyotrophic Lateral Sclerosis. A One-arm, Single-center, Proof-of-concept Study (Son-ALS)

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

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.

After the first sonication session only, a brain MRI will be performed with Gadolinium injection, to confirm BBB opening. Pre and post-sonication dosing of serum NfL and markers of BBB disruption will also be performed after the first sonication visit.

Eight additional ultrasound session visits will be performed at three-week intervals. At the fifth sonication visit (W14), motor function evaluation (ALSFRS-R and manual muscle testing), pulmonary function testing, blood samplings for serum NfL and ALSAQ-5 QOL evaluation will be performed before sonication.

At the last sonication (W26), clinical evaluation (ALSFRS-R, Manual muscle testing), pulmonary function test and ALSAQ-5 quality of life evaluation will be performed before sonication as well as blood samplings for serum NfL and pre-explantation preoperative laboratory blood tests. After the last ultrasound session, the patient will be followed up for a total of 12 weeks.

The explantation visit will take place at week 28. Explantation will be performed in a dedicated surgical procedure under local anesthesia: skin opening, device removal, no dura matter opening. Before explantation motor function evaluation will be performed. After explantation, neurological evaluation and brain MRI will be performed for safety evaluation. The last visit is planned at week 38 and will be performed by the neurology team as an outclinic visit (neurological examination, evaluation of motor function, ALSAQ-5 quality of life evaluation).

After this last visit, patients will resume their routine follow-up. Vital status and date of last known contact will be documented at the end of the study for all participants (at the last visit of the last patient included).

Inclusion Criteria:

1. Age 18-80 years,
2. Able and willing to give signed and informed consent
3. 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)
4. Disease duration <= 36 months,
5. Mild functional impairment (ALSFRS-R ≥30),
6. 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,
7. Slow Vital capacity >= 70% of normal,
8. If taking riluzole, patient on stable dose for over 30 days prior to study entry,
9. Able and willing to follow trial procedures including site travels and visit requirements

Exclusion Criteria:

1. 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
2. Cardiac pacemaker (contraindication to MRI)
3. Allergy to any drug used in the study (Gadolinium, Xylocain, Cloxacilline, EMLA, echographic contrast agent microbubbles: SonoVue®)
4. Severe or instable chronic or acute disease or any life-threatening condition
5. Other significant neurological or psychiatric disease in addition to ALS, including history of uncontrolled seizures
6. 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
7. Invasive or non-invasive mechanical ventilation use
8. Gastrostomy or nasogastric tube use
9. Known right-to-left shunts,
10. Known severe pulmonary hypertension (pulmonary artery pressure >90 mmHg), uncontrolled systemic hypertension
11. Known respiratory distress syndrome
12. Women of child-bearing potential or sexually active man, without contraception
13. Pregnant or breast-feeding woman
14. 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.
15. Patient not affiliated or beneficiary of a social security category