Evaluation of Human Fetal Neural Precursor Cells and Tacrolimus in Progressive Multiple Sclerosis: A Randomized, Assessor-Blind, Multicenter Phase 2 Study

The primary objective of this study is to evaluate the **therapeutic efficacy** of human fetal neural precursor cells (hfNPCs) administered intrathecally in patients with **Progressive Multiple Sclerosis** (PMS). This involves two administrations of 200 x 10⁶ ±10% cells, spaced six months apart, compared to a sham procedure. The clinical relevance of this objective lies in its potential to offer a novel therapeutic approach for PMS, a condition characterized by progressive neurological decline and limited treatment options.

Secondary objectives include: - Evaluating the **safety** of hfNPCs in this patient population. - Further assessing the **efficacy** of the treatment regimen, which consists of two intrathecal administrations of 200 x 10⁶ ±10% cells, six months apart.

The clinical trial involves participants diagnosed with **Progressive Multiple Sclerosis** (PMS), as per the 2017 revised McDonald criteria. The study population includes both male and female subjects, aged between 18 and 65 years. Participants are required to have an Expanded Disability Status Scale (EDSS) score between 3.0 and 8.0 at screening. The trial population was selected based on their willingness and ability to provide informed consent, as well as their failure, intolerance, or ineligibility to approved therapies according to the disease course. Participants must be able to take oral medication and adhere to study procedures. Females of reproductive potential are required to use highly effective contraception for at least one month prior to screening and during the study, while males must use an effective birth control strategy and abstain from sperm donation throughout the study duration. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and both genders are represented. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, patient and assessor **blind**, multicentre study designed to evaluate the therapeutic efficacy of human fetal neural precursor cells (hfNPCs) transplantation compared to a sham procedure in patients with **progressive multiple sclerosis** (PMS). The trial involves two intrathecal administrations of 200 million cells, spaced six months apart. The primary endpoint is the change in whole brain volume evaluated through magnetic resonance imaging (MRI) over a 96-week follow-up period. Secondary endpoints include the rate and nature of adverse events, percentage changes in brain grey and white matter volumes, and various measures of disability progression and cognitive function.

The trial is expected to commence recruitment on August 30, 2024, and conclude by February 6, 2028. Participants will be involved in the study for a maximum of 96 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, diagnosis, and disease progression; baseline assessments; and follow-up visits at regular intervals to monitor safety and efficacy outcomes. The end-of-study visit will occur at the conclusion of the 96-week follow-up period.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to study procedures, or withdraw consent. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and meet the inclusion criteria, such as being between 18 and 65 years of age, having an Expanded Disability Status Scale (EDSS) score between 3.0 and 8.0, and demonstrating failure or intolerance to approved therapies. The study is not a low-intervention trial and is classified as a Phase 2 trial, focusing on a drug not currently authorized for the population involved.

The clinical trial involves the administration of **tacrolimus**, a chemical entity, as one of the experimental medications. Tacrolimus is provided in an oral pharmaceutical form, identified by the code PHF00170MIG. The maximum daily dose is 0.1 mg/kg, with a total maximum dose of 37.1 mg/kg over a treatment period of up to 53 weeks. The administration route is oral, and the medication is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The second experimental treatment involves the use of **human fetal neural precursor cells**. These cells are administered as a solution for infusion, specifically designed for intrathecal delivery. The maximum daily dose is 200 million cells, with a total maximum dose of 400 million cells over a treatment period of up to 2 weeks. The cells are derived from a structurally diverse substance, categorized under cell therapy, and are not intended for pediatric use. The administration schedule includes two intrathecal administrations, spaced six months apart, to evaluate the therapeutic efficacy in patients with progressive multiple sclerosis. Compliance with the administration schedule will be closely monitored to ensure the integrity of the trial outcomes.

The efficacy of the investigational treatment in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the change in whole brain volume, which will be evaluated through magnetic resonance imaging (MRI) over a follow-up period of 96 weeks. This measurement will provide insight into the potential impact of the treatment on brain atrophy in patients with progressive multiple sclerosis.

Secondary endpoints include a variety of measures to further assess the treatment's efficacy. These include the rate and nature of adverse events classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and the percentage change in brain grey and white matter volumes, also evaluated through MRI over 96 weeks. Additionally, the trial will assess the proportion of patients with no evidence of 24-weeks confirmed disability progression, as defined by changes in the Expanded Disability Status Scale (EDSS). Other secondary measures include the proportion of patients with no evidence of progression, defined by sustained stability in disability progression, timed 25-foot walk test, and nine-hole peg test over 96 weeks. The trial will also evaluate the proportion of patients with no active disease, characterized by the absence of clinical relapses and new or enlarging T2 hyperintense lesions, as well as gadolinium-enhancing lesions. Cognitive function changes will be measured using the symbol digit modalities test (SDMT) over the same follow-up period.