Phase 2 Randomized Double-Blind Study of ILB (Dextran Sulfate Low Molecular Weight) vs. Riluzole in Amyotrophic Lateral Sclerosis Patients

The primary objective of this study is to evaluate the **efficacy** of ILB® compared to Riluzole in reducing disease progression in participants with **Amyotrophic Lateral Sclerosis (ALS)**. This is clinically relevant as ALS is a progressive neurodegenerative disease, and slowing its progression can significantly impact patient outcomes and quality of life.

Secondary objectives include:

• Evaluating the efficacy of ILB® compared to Riluzole on reducing levels of axonal damage biomarkers, measured by Serum Nfl, and other axonal damage biomarkers.
• Assessing the impact on motor limb and bulbar function, lung function, and cognitive function.
• Evaluating the safety and tolerability of ILB® compared to Riluzole.
• Investigating the effects on health-related quality of life and patient-reported outcome measures.
• Studying the pharmacokinetics of ILB® compared to Riluzole.
• Evaluating the long-term efficacy on axonal damage biomarkers, disease progression, motoric limb and bulbar function, forced vital capacity (FVC), cognition, and health-related quality of life (HRQOL).
• Assessing overall survival (OS) and long-term safety and tolerability of ILB®.
• Exploring ILB® effects on exploratory biomarker activity and using advanced Magnetic Resonance Imaging (MRI) modalities.
• Studying the effects on long-term health-related quality of life and health-economic aspects.

The clinical trial focuses on evaluating the efficacy of ILB® compared to Riluzole in reducing disease progression in participants with **Amyotrophic Lateral Sclerosis** (ALS). The study population includes both male and female participants aged 18 to 80 years, who are in a stable health condition as determined by comprehensive medical evaluations. Participants must have been diagnosed with ALS according to the World Federation of Neurology revised Gold Coast criteria, with the onset of symptoms within 24 months prior to the screening visit. The trial does not involve a vulnerable population. Participants are required to have a Forced Vital Capacity (FVC) of at least 60% of the predicted value for their gender, height, and age, and an ALSFRS-R score of at least 28 points at screening. They must have started treatment with Riluzole at least two weeks before screening and be willing to pause this treatment 48 hours prior to the baseline visit. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **Phase 2, randomized, double-blind, double-dummy study** designed to evaluate the efficacy, safety, and biomarker effects of ILB® compared to Riluzole in participants with **Amyotrophic Lateral Sclerosis (ALS)**. The trial aims to assess the reduction in disease progression over a period of 48 weeks. Participants will be randomly assigned to receive either ILB® or Riluzole, with corresponding placebos to maintain blinding. The study will involve a total of 48 weeks of treatment, with the primary endpoint being the change in the Amyotrophic Lateral Sclerosis Functional Rating Scale (revised) (ALSFRS-R) score from baseline at week 24.

The trial will commence with a screening visit to determine eligibility based on specific inclusion criteria, such as age between 18 to 80 years, a diagnosis of ALS according to the World Federation of Neurology revised Gold Coast criteria, and a stable health condition. Participants must have started Riluzole treatment at least two weeks prior to screening and be willing to pause it 48 hours before the baseline visit. The baseline visit, designated as Day 1, will mark the start of the treatment phase. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and biomarker changes, with key assessments at weeks 24 and 48.

The expected length of participant involvement is approximately 48 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Secondary endpoints include changes in serum Nfl, urine P75ECD, serum N-acetyl-aspartate (NAA) concentrations, and other clinical and laboratory parameters. The study will also evaluate the incidence and severity of adverse events, as well as changes in cognitive and behavioral assessments. The end-of-study visit will occur at week 48, concluding the participant's involvement in the trial.

The clinical trial involves the administration of **ILB**, an experimental medication formulated as a **solution for injection**. The active substance in ILB is **dextran sulfate low molecular weight**, also known as low-molecular-weight dextran or low molecular dextran-L. This medication is administered via **subcutaneous injection**. The dosing regimen for ILB is set at a maximum daily dose of 1 mg/kg, with a total maximum dose of 48 mg/kg over a treatment period of 48 weeks. ILB is classified as a neuroprotectant and is being evaluated for its efficacy in reducing disease progression in participants with **amyotrophic lateral sclerosis** (ALS).

The study also includes a **placebo** for ILB, which serves as a control to assess the efficacy of the experimental treatment. The placebo is designed to mimic the administration of ILB without containing the active substance. The pharmaceutical form and route of administration for the placebo are not specified, but it is used in a double-blind manner to ensure unbiased results.

Additionally, the trial involves the use of **RILUTEK 50 mg film-coated tablets**, which contain the active substance **riluzole**. RILUTEK is administered orally, with a maximum daily dose of 100 mg and a total maximum dose of 16,800 mg over a 24-week treatment period. RILUTEK serves as a comparator treatment in the study, providing a standard-of-care reference against which the efficacy of ILB is measured.

A **placebo** for Riluzole capsules is also included in the trial. This placebo is used to maintain the double-dummy design of the study, ensuring that all participants receive both an injection and an oral tablet, whether active or placebo, to maintain blinding. The specific details regarding the pharmaceutical form and route of administration for the placebo Riluzole capsules are not provided.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The study is conducted under strict regulatory guidelines to evaluate the safety and efficacy of the investigational treatments in participants with ALS.

The efficacy of the investigational product ILB® compared to Riluzole in participants with **Amyotrophic Lateral Sclerosis (ALS)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in the Amyotrophic Lateral Sclerosis Functional Rating Scale (revised) (ALSFRS-R) score from baseline at week 24. This scale is a validated tool used to measure the functional status of ALS patients.

Secondary endpoints include various biomarker assessments and clinical measures. These include changes in serum neurofilament light chain (Nfl) levels, the concentration of the extracellular domain of p75 (P75ECD) in urine, and serum N-acetyl-aspartate (NAA) concentration from baseline to week 24. Additionally, changes in the Modified Norris Scale scores, forced vital capacity (FVC) scores, and Edinburgh Cognitive and Behavioral ALS screen (ECAS) scores will be evaluated. Patient-reported outcomes will be measured using the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) and the EuroQol-5-Dimension-5-Levels questionnaire (EQ-5D-5L).

Further assessments include the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as clinically meaningful changes in laboratory parameters, vital signs, and electrocardiogram (ECG) results. Pharmacokinetic parameters of ILB® will be evaluated in approximately 10 participants. Long-term efficacy will be assessed by measuring changes in serum Nfl, NAA, and P75ECD in urine at week 48, as well as the mean change from baseline in ALSFRS-R score, Modified Norris Scale scores, FVC scores, ECAS score, ALSAQ-40, and EQ-5D-5L at week 48.

Additional exploratory endpoints include overall survival (OS), assessed by time from baseline to death from any cause or tracheostomy, and biomarker activity changes of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and glutamate from baseline to week 24 and week 48. MRI changes will be evaluated in selected 50 participants with ALS at week 24 and week 48. Healthcare utilization data, including hospital stays and emergency room visits, will be collected, and health-related quality of life (HRQOL) will be assessed with ALSAQ-40 and EQ-5D-5L. Economic analysis will assess changes in healthcare usage using both within-trial and model-based approaches, with an emphasis on long-term projections.