Preclinical and clinical data strongly suggest that administration of salbutamol in ALS patients may improve walking capacity related to motor fatigue by enhancing neuromuscular transmission. Salbutamol may exert a neuroprotective effect and slow down the progression of clinical signs and symptoms. The main objective of the study is to test the efficacy of salbutamol on walking capacity in ALS patients and the secondary objective is to measure the target engagement of salbutamol on the neuromuscular junction (NMJ) at EMG (decrement of repetitive nerve stimulation in three nerves/muscle couples), as well as safety and tolerability. The exploratory objectives are to study the effect of salbutamol on fatigue scales, muscle strength, respiratory function, motor unit count, muscle and spinal MRI parameters and blood biomarkers

Based on a strong preclinical and clinical rationale the main hypothesis is that the administration of salbutamol in ALS patients may improve the walking capacity related to motor fatigue by enhancing the neuromuscular transmission. Salbutamol may also exert a neuroprotective effect and slow down the progression of clinical signs and symptoms.

To test these hypotheses, the investigator team will implement a monocentric, randomized, controlled, pilot study to evaluate the effect of salbutamol on walking capacity in ambulatory ALS patients with a total duration of 24 months and a treatment period of 6 months for each patient. The project Team will use as secondary and exploratory endpoints target engagement and efficacy up-to date biomarkers such as quantitative muscle strength evaluation, functional neuromuscular evaluation and spinal and muscle MRI. Tolerability and safety will also be studied. Salbutamol has been used for a long time and is usually well tolerated. The objective of the study is to evidence a signal of efficacy paving the way for a confirmatory phase 3 trial.

In parallel to this, the use of muscle and spinal MRI as well as of quantitative muscle strength evaluation as exploratory endpoints will pave the way to their development as biomarkers of disease progression in ALS. Thanks to the data collected in this study, the team will give proof of their accuracy, with a view to ameliorate the prognostication and monitoring of disease progression and survival, as well as to improve the understanding of the interaction between muscular and central degeneration. A further aim of this study will be to provide a proof of concept that spinal and muscle MRI can constitute a biomarker of the efficacy of investigational drugs targeting muscles.

Inclusion Criteria:

• Subjects who meet the revised El Escorial criteria for probable or definite sporadic ALS
• Adult patients between 18 and 75 years of age
• Patients who are ambulatory and able to perform the 6MWT and quantitative muscle testing at screening (ALSFRS-R-walking = 3)
• Patients able and willing to travel to the site, and, in the investigator's opinion, who are likely to attend visits for at least 6 months
• Patients who signed written informed consent
• Stable dose of riluzole for a minimum of 4 weeks prior to baseline or has not taken it for 4 weeks prior to baseline
• For child-bearing aged women, efficient contraception (cf protocol p32)
• Forced vital capacity (fVC) in a sitting position > 70 %

Exclusion Criteria:

• Patients with significant spasticity of the lower limbs interfering with walking capacity (Ashworth scale score > 2)
• Patients with fronto-temporal dementia associated with ALS
• Patients presenting respiratory insufficiency causing dyspnea during walking
• Patients taking drugs that could interfere with NMJ function (anticholinesterase …) or muscle function (steroids, statins…)
• Patients taking any forbidden drugs (see list in annex)
• Hypersensitivity to salbutamol or to excipients of the drug and placebo
• Known contraindication for the studied drug such as ischemic cardiomyopathy or risk of ischemic cardiomyopathy: history of ischemic heart disease or coronaropathy or/and significant ischemic ECG alterations at screening visit
• Any clinically significant alterations in the following biological parameters glycemia, kalemia, creatinemia and hematology in the month prior to inclusion according to local laboratory threshold (cf protocol page 33)
• Vulnerable persons defined in Articles L1121-5 to L 1121-8-1 and L1122-1-2 of the Code de la Santé Publique* (*CSP)
• Participation in another interventional trial up to 3 months before inclusion
• Patients having any relevant concomitant disease considered at risk of interfering with study procedures in the opinion of the investigator