Evaluation of Bacillus Calmette-Guérin Vaccine in Patients with Radiologically Isolated Syndrome: A Randomized Controlled Trial

The primary objective of this study is to assess the cumulative number of combined unique new active lesions (**CUAL**), defined as new gadolinium T1-weighted and T2-weighted new and newly non-enhancing expansion, on magnetic resonance imaging (MRI) scans over a period of 1 year in patients with Radiologically Isolated Syndrome (**RIS**). This is clinically relevant as it provides insight into the progression of RIS, potentially aiding in early intervention strategies.

Secondary objectives include:

• Evaluating the time to the first clinical event over a 3-year period.
• Exploratory assessments of the number of cortical lesions, Percentage of Brain Volume Changes (**PBVC**), and cortical and white matter volume changes at 6 months, as well as at 1, 2, and 3 years.
• Evaluating the Magnetization Transfer ratio (**MTr**) in lesions and normal-appearing brain at 6 months, as well as at 1, 2, and 3 years.
• Assessing the overall safety and tolerability profile of the BCG 10 Anti-Tuberculosis Vaccine administered intradermally in subjects with RIS diagnosis.

The clinical trial involves participants diagnosed with **Radiologically Isolated Syndrome (RIS)** within the last five years. The study population includes both male and female subjects of any race, all of whom are over 18 years of age. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their diagnosis of RIS and their ability to provide signed informed consent. The trial includes a vulnerable population, although specific lifestyle considerations such as diet, physical activity, or habits have not been detailed. The study does not specify any additional key inclusion or exclusion criteria beyond the diagnosis and consent requirements.

The clinical trial is designed to evaluate the efficacy and safety of the **BCG vaccine** in individuals diagnosed with **Radiologically Isolated Syndrome (RIS)**. This is a Phase 4, randomized, double-blind, controlled trial. The study aims to assess the cumulative number of combined unique new active lesions (CUAL) on magnetic resonance imaging (MRI) scans over a period of one year. The trial is expected to run from July 29, 2019, to July 30, 2026, with participant involvement lasting up to three years, including follow-up assessments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (over 18 years), a diagnosis of RIS within the last five years, and the provision of signed informed consent. Following randomization, participants will receive either the BCG vaccine or a placebo, administered via intradermal injection. The primary endpoint is the cumulative number of CUAL on MRI scans over one year, while secondary endpoints include the time to the first clinical event within a three-year period, the number of cortical lesions, and changes in brain volume and magnetization transfer ratio (MTr).

Study visits will include regular follow-up assessments to monitor safety and efficacy, with adverse events and laboratory tests being key safety endpoints. The end-of-study visit will conclude the participant's involvement, unless early termination is warranted due to adverse events, withdrawal of consent, or other protocol-specified conditions. The trial's design ensures rigorous monitoring and data collection to achieve its objectives, contributing valuable insights into the management of RIS.

The clinical trial involves the administration of two treatments. The first treatment is **Sodium Chloride** 0.9% solution, marketed under the name "Sodio cloruro S.A.L.F. 0,9% solvente per uso parenterale." This product is a **solvent for parenteral use** and is manufactured by S.A.L.F. SPA Laboratorio Farmacologico. The pharmaceutical form is a solvent, and it is administered via **intradermal use**. The maximum daily dose is 50 microliters, with a total maximum dose of 50 microliters over a treatment period of one day. This solution is isotonic and serves as a non-experimental treatment in the study, potentially acting as a placebo or comparator treatment.

The second treatment is the "BCG 10 Anti-Tuberculosis Vaccine, Powder and solvent for suspension for intradermal injection Vaccinum tuberculosis (BCG) cryodesiccatum." This vaccine is produced by BIOMED-LUBLIN WSISZ S.A. and contains the active substance **Live BCG Bacilli (Bacillus Calmette-Guérin), Brazilian Moreau substrain**. The pharmaceutical form is a suspension for injection, and it is also administered via **intradermal use**. The dosing schedule allows for a maximum daily dose of 50 microliters, with a total maximum dose of 50 microliters over a one-day treatment period. This vaccine is the experimental medication in the trial, designed to assess its efficacy in the context of the study's objectives.

The efficacy of the clinical trial titled "Bacille Calmette-Guérin (BCG) Vaccine in Radiologically Isolated Syndrome (RIS)" will be assessed primarily through the cumulative number of combined unique new active lesions (CUAL) on magnetic resonance imaging (MRI) scans over a period of one year. This primary endpoint is defined by the presence of new gadolinium T1-weighted and T2-weighted new and newly non-enhancing expansion lesions. Secondary endpoints include the time to the first clinical event within a three-year period, the number of cortical lesions, the percentage of brain volume changes (PBVC), changes in the volume of the cortex and white matter, and the magnetization transfer ratio (MTr) in lesions and normal-looking brain tissue. Safety and tolerability will also be evaluated through the monitoring of adverse events and laboratory tests conducted during the study.