Phase III Randomized Double-Blind Crossover Study of N-Acetyl-L-Leucine in Niemann-Pick Disease Type C

The primary objective of this study is to evaluate the **efficacy** of N-Acetyl-L-Leucine in the chronic treatment of Niemann-Pick disease type C (NPC) using the Scale for the Assessment and Rating of Ataxia (SARA). This is clinically relevant as it aims to determine the potential of N-Acetyl-L-Leucine to improve motor function and reduce ataxia symptoms in patients with NPC, a rare and progressive neurodegenerative disorder.

Secondary objectives include:

• Assessing the clinical efficacy of N-Acetyl-L-Leucine on symptoms, functioning, and quality of life for patients with NPC.
• Evaluating the safety and tolerability of N-Acetyl-L-Leucine at a dosage of 4 g/day in NPC patients aged 13 years and older, and weight-tiered doses in NPC patients aged 4 to 12 years.

The clinical trial involves a total of **60 participants** diagnosed with **Niemann-Pick disease type C**. The study population includes both male and female subjects aged 4 years and older, with a confirmed diagnosis of the disease. Participants were selected based on specific criteria, including a Scale for the Assessment and Rating of Ataxia (SARA) score between 7 and 34 points, and the ability to perform certain motor function tests within defined parameters. The trial population is characterized by individuals who are part of a vulnerable group due to their medical condition. Participants must weigh at least 15 kg at the time of screening. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that all participants have provided written informed consent, either personally or through a legal representative.

The clinical trial is a **Phase III**, randomized, placebo-controlled, double-blind, crossover study designed to evaluate the efficacy of **N-Acetyl-L-Leucine** in the treatment of **Niemann-Pick disease type C** (NPC). The primary objective is to assess the efficacy of the investigational product using the Scale for the Assessment and Rating of Ataxia (SARA) for chronic treatment. The trial is expected to run from July 2022 to December 2027, with a maximum treatment period of 116 days per participant. Participants will be randomly assigned to receive either the investigational product or a placebo in a crossover design, ensuring that each participant receives both treatments at different periods.

Study visits are structured to include an initial screening visit, followed by multiple follow-up visits, and concluding with an end-of-study visit. The inclusion visit involves obtaining written informed consent and confirming eligibility criteria, such as age, diagnosis of NPC, and specific SARA score requirements. Follow-up visits are scheduled to monitor the participants' response to treatment and assess primary and secondary endpoints, including the Spinocerebellar Ataxia Functional Index (SCAFI) and Quality of Life assessments. The end-of-study visit will evaluate the overall treatment effects and gather final data.

Participant involvement is expected to last for the duration of the treatment period, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with study protocols. The trial's design ensures that all participants receive both the investigational product and placebo, allowing for a comprehensive evaluation of the treatment's efficacy and safety. The study's endpoints and methodology are aligned with regulatory standards to ensure the reliability and validity of the findings.

The clinical trial involves the administration of **N-Acetyl-L-Leucine**, an experimental medication formulated as an **oral suspension**. The active substance, **L-Acetylleucine**, is of chemical origin and is provided by INTRABIO LIMITED. The medication is administered orally with a maximum daily dose of 4 grams. The treatment period extends up to 116 days. The primary objective of the trial is to evaluate the efficacy of N-Acetyl-L-Leucine in the treatment of Niemann-Pick disease type C (NPC), utilizing the Scale for the Assessment and Rating of Ataxia (SARA) as a measure of efficacy. Participant compliance with the dosing schedule is monitored throughout the study.

In addition to the experimental treatment, the study employs a **placebo** as a comparator. The placebo is presented in the form of granules for oral suspension. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This design allows for an unbiased assessment of the experimental medication's efficacy and safety. The placebo is administered following the same schedule as the experimental treatment to ensure consistency in the trial protocol.

The efficacy of N-Acetyl-L-Leucine in the treatment of **Niemann-Pick disease type C (NPC)** will be assessed using several parameters. The primary endpoint is the Scale for the Assessment and Rating of Ataxia (SARA), with the Modified SARA being used in the United States. This scale is a validated tool for measuring ataxia severity and will be used to evaluate the chronic treatment effects of the investigational product. Secondary endpoints include the Spinocerebellar Ataxia Functional Index (SCAFI), Quality of Life assessments using EQ-5D-5L for patients aged 18 and older, and EQ-5D-Y for those under 18, the Modified Disability Rating Scale (mDRS), and the Clinical Global Impression of Improvement (CGI-I) as reported by physicians, caregivers, and patients where applicable.

Efficacy assessments will be conducted at specific timepoints throughout the trial. The CGI-I will compare the end of period I (Visit 4) to baseline (Visit 2), and the end of period II (Visit 6) to the end of period I (Visit 4). These assessments will provide a comprehensive evaluation of the treatment's impact on patient function and quality of life. The trial is designed as a Phase III, randomized, placebo-controlled, double-blind, crossover study, ensuring rigorous evaluation of the treatment's efficacy in a controlled setting.