Evaluation of Deferiprone's Efficacy on Gross Motor Function in Pediatric Pelizaeus-Merzbacher Disease: A Proof-of-Concept Clinical Trial

The primary objective of this study is to evaluate the effect of **deferiprone** on gross motor function in children with Pelizaeus-Merzbacher disease (PMD). This is clinically relevant as PMD is a rare genetic disorder affecting the central nervous system, leading to motor function impairments. Improving gross motor function can significantly enhance the quality of life and daily functioning of affected individuals.

Secondary objectives include: - Assessing the effect of deferiprone on myelination and white matter integrity using quantitative brain MRI parameters, such as Diffusion Tensor Imaging (DTI), Chemical Shift Imaging (CSI), Neurite Orientation Dispersion and Density Imaging (NODDI), and Myelin Water Fraction Imaging (MWFI). - Evaluating the impact of deferiprone on clinical parameters, including the Health Utility Index (HUI), Manual Ability Classification System (MACS), Communication Function Classification System (CFCS), and Eating and Drinking Ability Classification System (EDACS). - Investigating the effect of deferiprone on functional central nervous system connectivity through EEG.

The clinical trial focuses on evaluating the effect of deferiprone on gross motor function in children diagnosed with **Pelizaeus-Merzbacher disease** (PMD). The study population consists exclusively of male participants, aged 8 years or younger, who have a genetically confirmed diagnosis of PMD. This includes individuals with a hemizygous clinically relevant missense mutation in the PLP1 gene or a PLP1 triplication or higher copy numbers, along with a brain MRI compatible with the diagnosis. Participants are required to live within a reasonable travel distance from Amsterdam and must have the possibility of weekly capillary blood sampling at or close to home. The trial specifically targets those with the connatal or classic form of the disease, characterized by the inability to sit without support and/or a mutation predicting this form. The sponsor has not provided information regarding the total number of participants involved in the study.

The clinical trial is designed to evaluate the effect of **deferiprone** on gross motor function in children diagnosed with Pelizaeus-Merzbacher disease (PMD). This is a Phase II, randomized, double-blind, controlled study. The trial will span approximately three years, with an estimated recruitment start date of May 3, 2024, and an estimated end date of May 3, 2027. Participants will be administered Ferriprox 100 mg/ml oral solution, with a maximum daily dose of 25 mg/kg, for a treatment period of up to one year.

The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the **screening** visit, eligibility will be assessed based on criteria such as age, genetic confirmation of PMD, and proximity to the study site. Follow-up visits will occur at regular intervals to monitor motor function using the Gross Motor Function Measurement tool (GMFM-88) and other secondary endpoints, including quantitative brain MRI parameters and electrophysiological assessments. The end-of-study visit will conclude the participant's involvement, with a final evaluation of the primary and secondary endpoints.

Participant involvement is expected to last for the duration of the treatment period, up to one year, with regular monitoring throughout. Conditions that may lead to early termination from the study include adverse reactions to the medication, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide valuable insights into the potential efficacy of deferiprone in improving motor function in children with PMD, contributing to the understanding and management of this rare disease.

The clinical trial involves the administration of **Ferriprox 100 mg/ml oral solution**, which contains the active substance **deferiprone**. This experimental medication is formulated as an oral solution and is intended for **oral use**. The dosage is specified as 25 mg/kg, with a maximum daily dose of 25 mg/kg. The treatment period is limited to a maximum of one day. Deferiprone functions as a chelator and is chemically derived. The product is manufactured by Chiesi Farmaceutici S.p.A. and is authorized under the marketing authorization number EU/1/99/108/003. The ATC code for deferiprone is V03AC02, indicating its classification as a chelating agent.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of deferiprone in patients with Pelizaeus-Merzbacher disease (PMD). Participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed regimen. The trial aims to assess the impact of deferiprone on gross motor function in children diagnosed with PMD.

Efficacy in this clinical trial will be assessed by evaluating the effect of **deferiprone** on gross motor function in children with Pelizaeus-Merzbacher disease (PMD). The primary endpoint for efficacy evaluation is motor function, which will be measured using the Gross Motor Function Measurement tool (GMFM-88) and the GMF scoring for metachromatic leukodystrophy (MLD-GMF score). These tools are validated scales that provide a comprehensive assessment of motor abilities.

Secondary endpoints include a range of quantitative and clinical parameters. Quantitative brain MRI parameters will be assessed using Diffusion Tensor Imaging (DTI), Chemical Shift Imaging (CSI), Neurite Orientation Dispersion and Density Imaging (NODDI), and Myelin Water Fraction Imaging (MWFI). Electrophysiological parameters will be evaluated through EEG. Clinical parameters will encompass general health and quality of life, assessed by the Health Utility Index (HUI), and hand function, measured by the Manual Ability Classification System (MACS). Additional assessments will include the Communication Function Classification System (CFCS), Swallowing function via the Eating and Drinking Ability Classification System (EDACS), Euro-Quality of Life Instrument 5D, 5 levels (EQ-5D-Y, proxy), and the Vineland Adaptive Behavior Scales, 3rd edition (Vineland-3).