Randomized Phase II/III Trial Evaluating Acetylcarnitine Hydrochloride on Functional Disability Progression in Amyotrophic Lateral Sclerosis Patients

The primary objective of this randomized, phase II/III trial is to assess the **efficacy** of acetyl-L-carnitine (ALCAR) at dosages of 1.5g/day and 3g/day on the progression of functional disability in patients with **amyotrophic lateral sclerosis** (ALS). This is measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), which is clinically relevant as it evaluates the loss of self-sufficiency, a critical aspect of ALS progression.

Secondary objectives include evaluating the effect of ALCAR treatment on various clinical aspects: functional decline as measured by the ALSFRS-R total score, decline of forced vital capacity (FVC), quality of life as measured by the ALSAQ-40 scale, cognitive function as measured by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) scale, and survival (being alive and without tracheostomy). Additionally, the study aims to measure the effects of ALCAR on disease biomarkers potentially involved in the drug's mechanisms of action, including PGC-1 alpha, 3-nitrotyrosine (3-NT), acetyl cyclophilin A (acetyl-PPIA), neurofilament light chain (NFL), creatine kinase (CK), Musclin/osteocrin, MyomiRNA (MiR-206), uric acid, matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), and 4-hydroxynonenal (HNE). The study also seeks to evaluate the tolerability and safety of ALCAR treatment by identifying unexpected adverse events.

The clinical trial involves a total of **10 participants** diagnosed with **amyotrophic lateral sclerosis** (ALS). The study population includes both male and female subjects aged 18 years and older. Participants are required to have intact cognitive function and a confirmed ALS diagnosis according to the Gold Coast Criteria. The trial excludes vulnerable populations and focuses on individuals with a disease duration of 24 months or less from symptom onset. Participants must demonstrate self-sufficiency, satisfactory respiratory function, and documented progression of symptoms as measured by the ALSFRS-R scale. Additionally, they must have been treated with riluzole 50 mg twice daily for at least four weeks prior to the randomization visit. The selection process ensures that participants can understand and comply with study requirements and provide informed consent personally or through a legally authorized representative.

The clinical trial is designed to evaluate the **efficacy** of acetyl-L-carnitine in patients with **amyotrophic lateral sclerosis** (ALS). This is a randomized, double-blind, placebo-controlled, phase II/III trial. Participants will be randomly assigned to receive either acetyl-L-carnitine at dosages of 1.5g/day or 3g/day, or a placebo, administered as an oral solution. The trial aims to assess the progression of functional disability using the ALS Functional Rating Scale-Revised (ALSFRS-R) over a period of 48 weeks. The primary endpoint is the proportion of participants remaining self-sufficient after 48 weeks, while secondary endpoints include changes in ALSFRS-R scores, forced vital capacity (FVC), and quality of life measures.

The trial will commence with a screening visit to confirm eligibility based on criteria such as age, cognitive function, ALS diagnosis, and disease duration. Participants must have satisfactory bulbar, spinal, and respiratory function, and be on a stable dose of riluzole. Following successful screening, participants will be randomized and baseline assessments will be conducted. Study visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will take place at week 48, where final assessments will be conducted.

Participant involvement is expected to last approximately 48 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is anticipated to start recruitment in November 2024 and conclude by April 2027. The study is structured to ensure rigorous evaluation of the treatment's impact on ALS progression, with a focus on maintaining participant safety and data integrity throughout the trial duration.

The clinical trial involves the administration of **acetylcarnitine hydrochloride**, marketed under the name Nicetile 500 mg polvere per soluzione orale. This experimental medication is provided in the form of an **oral solution**. The active substance, acetylcarnitine hydrochloride, is of chemical origin and is administered orally. Participants in the trial will receive the medication at two different dosages: 1.5 grams per day and 3 grams per day. The maximum daily dose is set at 3 grams, with a total maximum dose of 1 gram per administration. The treatment period is limited to a maximum of 48 weeks. The medication is manufactured by ALFASIGMA S.P.A. in Italy and is identified by the ATC code N06BX12, which classifies it under acetylcarnitine. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in the study. The placebo is designed to mimic the experimental medication in appearance but contains no active substance. It serves as a control to assess the efficacy of acetylcarnitine hydrochloride in the progression of functional disability in patients with Amyotrophic Lateral Sclerosis (ALS). The placebo is administered in a manner consistent with the experimental treatment to maintain the integrity of the trial's blinding process. The use of a placebo is critical in determining the true therapeutic effects of the experimental medication.

The efficacy of acetyl-L-carnitine (ALCAR) in the treatment of **Amyotrophic Lateral Sclerosis (ALS)** will be assessed through a randomized, phase II/III clinical trial. The primary endpoint for evaluating efficacy is the proportion of participants remaining self-sufficient after 48 weeks, as determined by scores of three or higher in the ALS Functional Rating Scale-Revised (ALSFRS-R) items for swallowing, cutting food, handling utensils, and walking. Secondary endpoints include the mean change in ALSFRS-R total score, Forced Vital Capacity percentage (FVC%), and the five domains of the ALS Assessment Questionnaire-40 (ALSAQ-40) from baseline to week 48. Additional secondary endpoints involve the mean change in the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) total score, cumulative probabilities of remaining self-sufficient, free from a significant decline in ALSFRS-R score, without gastrostomy, and without non-invasive ventilation support during the 48-week period. Biomarker levels, such as PGC-1 alpha, 3-NT, and others in peripheral blood mononuclear cells and plasma, will also be measured. The number of adverse and serious adverse events will be recorded throughout the treatment period.