An open-label, non-randomized, extension study to further investigate the long-term efficacy, safety, and tolerability of Guanabenz in patients with early childhood onset vanishing white matter (VWM)

The primary objective is to evaluate the long-term efficacy of guanabenz in patients with early childhood onset (≤ 6 years) vanishing white matter disease as compared to matched historical controls. This assessment is clinically relevant for determining whether guanabenz provides sustained therapeutic benefit in this rare leukodystrophy characterized by progressive white matter degeneration.

The secondary objectives include:

• To identify overall survival in patients with vanishing white matter disease receiving guanabenz as compared to matched historical controls.

• To determine how disability and quality of life change over time in patients with vanishing white matter disease receiving guanabenz as compared to matched historical controls.

• To identify how MRI parameters relevant to brain white matter integrity change over time in patients with vanishing white matter disease receiving guanabenz.

• To evaluate the pharmacokinetic profile of guanabenz in vanishing white matter disease patients, and compare the pharmacokinetic profiles of the VWM1 guanabenz capsules versus the new batch of guanabenz capsules used in VWM2.

• To investigate plasma guanabenz levels for determination of the optimal guanabenz treatment dose.

• To evaluate the long-term safety and tolerability profile of guanabenz in patients with vanishing white matter disease.

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population includes both **male** and **female** subjects diagnosed with **vanishing white matter** disease. Eligible participants are categorized within pediatric and adolescent age ranges. The trial population was selected based on prior completion of the VWM1 study and geographic proximity to Amsterdam, ensuring reasonable travel distance for study visits. Key inclusion criteria require parental or legal guardian consent, willingness to participate in scheduled assessments either on-site or via video consultation, and ability to maintain contact with the study site throughout the trial duration while adhering to protocol-specified requirements. This study does not involve vulnerable populations.

This clinical trial is designed as an open-label, non-randomized, extension study to investigate the long-term efficacy, safety, and tolerability of guanabenz acetate in patients with early childhood onset vanishing white matter disease. The study follows participants who have completed a previous trial (VWM1 study) and aims to evaluate the continued therapeutic effects of guanabenz compared to matched historical controls. The investigational medicinal product consists of capsules containing guanabenz acetate in various dose strengths (1 mg, 2 mg, 4 mg, 8 mg, 16 mg, and 24 mg) administered via the oral route. Guanabenz acetate is classified as an antiadrenergic agent, centrally acting, and has been designated as an orphan drug (EU/3/23/2764) for this rare condition. The trial is categorized as a Phase I and Phase II integrated clinical trial, representing therapeutic exploratory and confirmatory investigation.

The primary objective of this extension study is to evaluate the long-term efficacy of guanabenz in patients with early childhood onset vanishing white matter disease, specifically those diagnosed at or before 6 years of age. The primary endpoint focuses on ambulation, measuring the change from baseline at the start of the VWM1 study to the end of the VWM2 study in the ability to walk at least 10 steps without and with light support of one hand. This assessment utilizes clinical examination tools including the Gross Motor Function Measure, version 88 (GMFM 88), item E, number 68-88, or the Health Utility Index (HUI) item 9, score 1-4, depending on available data in historical controls.

Secondary endpoints encompass multiple dimensions of disease progression and treatment response. Overall survival rate will be monitored throughout the study period. Changes in quality of life and disability will be assessed from the start of VWM1 to the end of VWM2 using comprehensive evaluation instruments including GMFM 88, GMFC-MLD, GMFCS, MACS, CFCS, ELFC-MLD, EDACS, HUI, LIPS, Vineland-3, EQ-5D-5L, and EQ-5D-Y (proxy and self-reporting from 8 years old). Neuroimaging parameters will be evaluated through changes in brain MRI from baseline at VWM1 study start to the end of the VWM2 study, utilizing advanced imaging techniques including Diffusion Tensor Imaging (DTI), Chemical Shift Imaging (CSI), Neurite Orientation Dispersion and Density Imaging (NODDI), and Myelin Water Fraction Imaging (MWFI). Pharmacokinetic parameters of guanabenz in plasma will be determined, including Cmax, AUC, half-life (T1/2), and predicted trough concentration (Ctrough) at steady state. The relationship between guanabenz exposure and the primary endpoint will be analyzed. Safety monitoring will include the frequency, severity, and daily life impact of all adverse events, including adverse events of special interest, occurring from the start of VWM2 study treatment until the end of the VWM2 study.

Principal inclusion criteria require that each patient's parents or legal guardians sign an informed consent form indicating understanding of the study purpose and procedures, willingness for their child to participate and attend all scheduled assessments (on site or by video consultation as indicated per protocol), and ability to comply with all study-related procedures, including maintaining contact with the site for the duration of the trial and adhering to protocol prohibitions and restrictions. Patients must have completed the VWM1 study and live within reasonable travel distance from the study center. No principal exclusion criteria are specified in the available documentation.

The estimated recruitment start date for this extension study is December 1, 2025, with an estimated study completion date of November 30, 2029, resulting in an overall trial duration of approximately 4 years. The total duration of participant involvement extends from their enrollment in the original VWM1 study through completion of the VWM2 extension study, allowing for comprehensive long-term evaluation of treatment effects. Study visits will include scheduled assessments conducted either on site or by video consultation as specified in the protocol, with requirements for participants to maintain regular contact with the study site throughout the trial period. Conditions that may lead to early termination from the study would be determined according to protocol-specified criteria, though specific termination conditions are not detailed in the available information.

The experimental medication utilized in this clinical trial is guanabenz acetate, a centrally acting antiadrenergic agent with alpha-2 adrenergic agonist properties. The investigational medicinal product has been designated as an orphan drug under the designation number EU/3/23/2764. Guanabenz acetate is provided in multiple capsule formulations to allow for flexible dosing across the study population. The pharmaceutical form consists of capsules containing varying strengths of the active substance in different blend compositions. The available dosage strengths include 1 mg in 90 mg blend, 2 mg in 180 mg blend, 4 mg in 360 mg blend, 8 mg in 160 mg blend, 16 mg in 320 mg blend, and 24 mg in 480 mg blend. The route of administration for all formulations is oral. The active substance is of chemical origin and is formulated to facilitate administration in patients with early childhood onset vanishing white matter disease.

The clinical trial is designed as an open-label, non-randomized extension study, which indicates that all participants receive the experimental treatment without comparison to a placebo or active comparator within the study itself. The evaluation of long-term efficacy is conducted through comparison with matched historical controls rather than through concurrent randomization to different treatment arms. This study design allows for the assessment of the investigational product's long-term safety, tolerability, and efficacy profile in the target patient population over an extended treatment period.

The primary efficacy endpoint is ambulation, measured as the change from baseline at the start of the VWM1 study to the end of the VWM2 study in the ability to walk at least 10 steps without and with light support of one hand. This will be assessed by clinical examination using the Gross Motor Function Measure, version 88 (GMFM 88), item E, number 68-88, or the Health Utility Index (HUI) item 9, score 1-4, depending on available data in historical controls. The long-term efficacy of guanabenz in patients with early childhood onset vanishing white matter will be evaluated by comparison to matched historical controls.

Secondary efficacy endpoints include overall survival rate and changes in quality of life and disability of participants, measured from the start of VWM1 to the end of VWM2. These assessments will be conducted using multiple validated instruments: GMFM 88, GMFC-MLD, GMFCS, MACS, CFCS, ELFC-MLD, EDACS, HUI, LIPS, Vineland-3, EQ-5D-5L, and EQ-5D-Y (proxy and self-reporting from 8 years old). Changes in brain MRI parameters from baseline at VWM1 study start to the end of the VWM2 study will also be evaluated, including Diffusion Tensor Imaging (DTI), Chemical Shift Imaging (CSI), Neurite Orientation Dispersion and Density Imaging (NODDI), and Myelin Water Fraction Imaging (MWFI). Additionally, guanabenz exposure will be analyzed versus the primary endpoint.