B-cell depletion for the treatment of patients with amyotrophic lateral sclerosis (ALS) - A Randomized, Double-blind, Placebo controlled Pilot Study in Patients with Amyotrophic Lateral Sclerosis for the Evaluation of Efficacy and Safety of B-Cell Depletion with Rituximab (ABCD)

The primary objective of this study is to investigate whether **Rituximab** as an add-on treatment can reduce symptom progression in patients with **Amyotrophic Lateral Sclerosis (ALS)** compared to standard therapy alone. This is clinically relevant as ALS is a progressive neurodegenerative disease with limited treatment options, and slowing symptom progression could significantly impact patient quality of life and disease management.

Secondary objectives include:

• Further evaluation of ALS-related signs and symptoms.
• Assessment of safety and tolerability following treatment with Rituximab.
• Clinical evaluation of motor deficits, assessment of BMI, and evaluation of the slow vital capacity score.
• Evaluation of laboratory parameters and cognitive deficits.
• Monitoring of adverse events and serious adverse events throughout the trial duration.

The clinical trial involves participants diagnosed with **Sporadic Amyotrophic Lateral Sclerosis** (ALS). The study population includes both male and female subjects, aged 18 years and older. Participants are required to have a disease duration of sporadic ALS of 24 months or less after symptom onset, without progression to a permanent need for assisted ventilation. The trial population was selected based on their ability to attend study visits and their medication regimen, specifically a stable dose of riluzole. Participants must have a slow vital capacity of at least 75% of the predicted normal value for their gender, height, and age. The trial also considers lifestyle factors such as adherence to recommended standard vaccinations, excluding Hepatitis B, which is assessed at screening. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, ensuring that all participants have the capacity to give informed consent.

The clinical trial is designed to evaluate the efficacy and safety of **rituximab** as an add-on treatment for patients with sporadic **amyotrophic lateral sclerosis** (ALS). This study is a randomized, double-blind, placebo-controlled pilot trial. The primary objective is to assess whether rituximab can reduce symptom progression compared to standard therapy alone. The trial is expected to last until September 2027, with recruitment starting in September 2023. Participants will be involved in the study for a maximum of 79 weeks, with the treatment period lasting up to 55 weeks.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as disease duration, age, and medication stability. The inclusion criteria require a disease duration of ≤ 24 months, age ≥ 18 years, and a stable dose of riluzole. The screening visit will also include assessments of slow vital capacity and vaccination status. Following the screening, participants will be randomized to receive either rituximab or placebo, administered via intravenous infusion.

Study visits will occur at regular intervals to monitor the primary endpoint, which is the change in the ALS Functional Rating Scale - Revised (ALSFRS-R) from baseline to 79 weeks. Secondary endpoints include changes in ALSFRS-R at various time points, slow vital capacity, BMI, tracheostomy-free survival, and overall survival. Safety assessments will include laboratory parameters, B cell counts, and neuropsychological tests. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of all endpoints and safety data.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and are capable of attending study visits. The study aims to provide valuable insights into the potential benefits of rituximab for ALS patients, contributing to the understanding of B-cell depletion therapy in this context.

The clinical trial involves the administration of **Rituximab**, marketed as Rixathon 500 mg concentrate for solution for infusion. This experimental medication is a **concentrate for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 1000 mg, with a total dose not exceeding 1000 mg over a treatment period of 55 days. The product is manufactured by SANDOZ GMBH and is specifically labeled for the trial. Rituximab is a protein-based therapeutic agent used to evaluate its efficacy and safety in reducing symptom progression in patients with amyotrophic lateral sclerosis (ALS).

In addition to the experimental treatment, the trial includes the use of **Methylprednisolone hydrogen succinate**, marketed as Methylprednisolon acis 1000 mg. This auxiliary medication is provided as a **solution for injection/infusion** and is administered via **intravenous injection**. The maximum daily dose is 100 mg, with a total dose not exceeding 100 mg over the same treatment period of 55 days. This synthetic glucocorticoid is manufactured by ACIS ARZNEIMITTEL GMBH and serves as a supportive treatment in the trial.

Another auxiliary treatment used in the study is **Sodium chloride**, marketed as Isotonische Kochsalzlösung Fresenius Infusionslösung. This product is a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 500 ml, with a total dose not exceeding 500 ml over 55 days. Manufactured by FRESENIUS KABI DEUTSCHLAND GMBH, sodium chloride serves as an electrolyte solution in the trial.

**Dimetindene**, marketed as Histakut Dimetindenmaleat 1 mg/ml, is also used as an auxiliary treatment. This medication is a **solution for injection** and is administered via **intravenous injection**. The maximum daily dose is 4 mg, with a total dose not exceeding 4 mg over the treatment period. Manufactured by GEBRO PHARMA GMBH, dimetindene is a synthetic metabolite used in the trial.

Lastly, **Paracetamol**, marketed as Paracetamol B. Braun 10 mg/ml Infusionslösung, is included as a placebo treatment. This product is a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 1000 mg, with a total dose not exceeding 1000 mg over 55 days. Manufactured by B.BRAUN MELSUNGEN AG, paracetamol is used to maintain blinding in the trial.

The efficacy of the clinical trial evaluating the use of **Rituximab** as an add-on treatment for patients with amyotrophic lateral sclerosis (ALS) will be assessed using several primary and secondary endpoints. The primary endpoint is the change in the ALS Functional Rating Scale - Revised (ALSFRS-R-SE) from baseline to 79 weeks after the administration of the first dose, compared to standard therapy with riluzole alone. Secondary endpoints include changes in ALSFRS-R-SE at various timepoints (3, 27, 53, 105, and 131 weeks), changes in slow vital capacity scores from baseline to 79 weeks, changes in BMI from baseline to 79 weeks, tracheostomy-free survival at 79 weeks, and overall survival in the Rituximab and standard therapy groups.

Additional secondary endpoints involve laboratory parameters evaluating the safety of Rituximab treatment, serum and cerebrospinal fluid analyses, B cell counts, neuropsychological tests (ECAS), and a Quality of Life questionnaire. These efficacy parameters will be measured and collected at specified intervals throughout the trial, with the primary focus on the 79-week mark. The trial is designed as a randomized, double-blind, placebo-controlled pilot study, with the primary objective of determining whether Rituximab can reduce symptom progression in ALS patients when used in conjunction with standard therapy.