Evaluation of Safety, Tolerability, and Pharmacokinetics of Guanabenz Acetate in Pediatric Patients with Early-Childhood Onset Vanishing White Matter

The primary objective of this study is to evaluate the **safety** and **tolerability** profile of guanabenz in pediatric patients with Vanishing White Matter (VWM). This is clinically relevant as it aims to ensure that guanabenz can be safely administered to this vulnerable population, potentially offering a therapeutic option for managing VWM, a progressive and often debilitating condition.

Secondary objectives include:

• Evaluating the pharmacokinetic (PK) profile of guanabenz in pediatric patients with VWM, which is crucial for understanding the drug's absorption, distribution, metabolism, and excretion in this specific population.
• Assessing how quantitative MRI parameters relevant to brain white matter integrity change over time in pediatric patients with VWM receiving guanabenz, providing insights into the drug's impact on brain structure.
• Evaluating changes in quality of life and disability over time in pediatric patients with VWM receiving guanabenz compared to historical controls, which is important for understanding the broader impact of the treatment on patient well-being.
• Assessing overall survival in pediatric patients with VWM receiving guanabenz compared to historical controls, which is a critical measure of the treatment's potential efficacy in extending life expectancy.

The clinical trial focuses on evaluating the safety and tolerability profile of guanabenz in pediatric patients diagnosed with **Vanishing White Matter** (VWM). The study population includes both male and female subjects, with an age range starting from 2 years. Participants are required to have a genetically confirmed diagnosis of VWM, with two clinically relevant mutations in one of the EIF2B1-5 genes, and a brain MRI compatible with the diagnosis. The disease onset must have occurred before the age of 6 years, and participants should be able to stand up and walk at least 10 steps with or without light support. The trial involves a vulnerable population, and the sponsor has not provided the total number of participants. Participants' parents or legal guardians must provide informed consent, indicating their understanding and willingness to comply with study procedures. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not disclosed the method of participant selection.

The clinical trial is designed to evaluate the **safety** and tolerability profile of **guanabenz acetate** in pediatric patients diagnosed with **Vanishing White Matter** (VWM). This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thereby minimizing bias. The trial is expected to span from May 31, 2021, to December 1, 2025, with participant involvement lasting between 1 to 4 years, depending on the time of entry into the trial.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a maximum disease duration of 8 years and disease onset before the age of 6 years. Following the screening, participants will attend regular follow-up visits to monitor safety and collect data on pharmacokinetic parameters, including Cmax, AUC, half-life, and predicted trough concentration at steady state. These visits will also involve quantitative brain MRI assessments and clinical evaluations to track disease progression and overall survival. The trial will conclude with an end-of-study visit to gather final data and ensure participant safety.

Participants are required to maintain contact with the study site and adhere to all study-related procedures. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or non-compliance with the study protocol. The primary endpoint focuses on the collection of all adverse events and serious adverse events, applying the National Cancer Institute Common Terminology Criteria for Adverse Events. The study aims to provide valuable insights into the potential efficacy of guanabenz in managing VWM, contributing to the development of therapeutic strategies for this condition.

The clinical trial involves the administration of **guanabenz acetate** in various dosages to evaluate its safety, tolerability, and potential efficacy in patients with early-childhood onset Vanishing White Matter (VWM). The experimental medication is provided in capsule form, with each capsule containing a specific dosage of guanabenz acetate. The available dosages for the trial include 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 16 mg, and 24 mg, each blended with a corresponding amount of excipient to form a complete capsule. The capsules are administered orally, and the frequency of administration is determined based on the study protocol. The guanabenz acetate used in this trial is of chemical origin and is classified as a synthetic drug. The capsules are not formulated specifically for pediatric use, although the trial focuses on pediatric patients.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as per the study design. However, specific details regarding these non-experimental treatments are not provided in the available data. The trial is conducted under the authorization of Amsterdam UMC, and the guanabenz acetate capsules are designated as an orphan drug, with the designation number EU/3/23/2764. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The study aims to gather comprehensive data on the pharmacokinetic profile of guanabenz acetate in the target patient population.

The efficacy of **guanabenz** in patients with early-childhood onset Vanishing White Matter (VWM) will be assessed through several secondary endpoints. These include pharmacokinetic (PK) parameters in plasma such as maximum concentration (Cmax), area under the curve (AUC), half-life, and predicted trough concentration (Ctrough) at steady state. Additionally, quantitative brain MRI parameters will be evaluated to assess changes in brain structure and function. Clinical parameters will also be monitored to determine the overall impact of the treatment on the disease progression. Overall survival will be measured as a key indicator of efficacy.