E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Progressive brain disorder mainly occurring in young children with early fatality. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
to evaluate the safety and tolerability profile of guanabenz in pediatric patients with VWM |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the PK profile of guanabenz in pediatric patients with VWM.
• To collect data on quantitative MRI parameters relevant to brain white matter integrity.
• To collect data on quality of life, disability and survival.
• To assess the relationship between guanabenz PK and safety/efficacy-related biomarkers, such as blood pressure, heart rate and MRI-based quantitative (continuous) markers of change in brain white matter integrity, in an exploratory PK/PD analysis.
• To collect blood and CSF for exploratory biomarker studies.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Each patient’s parents/legal guardians must sign an informed consent form (ICF) indicating that they understand the purpose of and procedures required for this study, are willing for their child to participate in the study and attend all scheduled visits, and are willing and able to comply with all study-related procedures, including maintaining contact with the site for at least 1 year, and adhere to the prohibitions and restrictions as specified in the protocol.
Note: For each patient, both parents/legal guardians must give written consent.
2. Male or female with a maximum disease duration at screening of 8 years.
3. Genetically proven VWM with 2 clinically relevant mutations in one of the EIF2B1-5 genes and a brain MRI compatible with the diagnosis.
4. Disease onset before the age of 6 years.
5. Able to stand up and walk at least 10 steps with or without the support of one hand.
Note: The “support of one hand” should be light. It does not refer to full support or to physically propelling the child forward.
6. Lives within reasonable travel distance from the VUmc site.
For historical controls:
1. Be in the same stratum as at least one patient included in the present study with respect to age at disease onset, disease duration at study entry, and disease severity category on the basis of the patient’s genotype.
2. VWM diagnosis after 2001, the year the gene defect for VWM was identified, after which it was realized that the defect affects the integrated stress response (ISR) and circumstances activating the ISR should be avoided, such as febrile infections.
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E.4 | Principal exclusion criteria |
1. Clinically asymptomatic.
2. Comorbidity with another genetic defect.
3. Presence of an unrelated serious condition (eg, developmental anomaly, cardiac, liver or kidney disease).
4. Participation in another clinical study with therapeutic intervention.
5. Unable or unwilling to come to the VUmc site as required by the protocol.
6. Unable to undergo MRI due to metal-containing implants, such as cochlea implant, neurostimulator or pacemaker.
7. Family situation in which adherence to the study medication or follow-up procedures cannot be guaranteed.
8. Known allergy or hypersensitivity to guanabenz or to any of the other components of the formulation used in this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• All adverse events and serious adverse events collected from the start of study treatment until the end of the study, applying the most recent version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, version 5.0, 27-Nov-2017). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1,5 years after FPI and end of study (approximately 4 years) |
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E.5.2 | Secondary end point(s) |
Secopndary end points include
• Guanabenz PK parameters, such as Cmax, AUC, half-life, and trough concentration (Ctrough), at steady state
• Quantitative brain MRI parameters:
Diffusion Tensor Imaging (DTI)
Chemical Shift Imaging (CSI)
Neurite Orientation Dispersion and Density Imaging (NODDI)
Myelin Water Fraction Imaging (MWFI)
• Clinical parameters:
Health Utility Index (HUI)
Gross Motor Function Classification – Metachromatic Leukodystrophy (GMFC-MLD)
Expressive Language Function Classification – Metachromatic Leukodystrophy (ELFC-MLD)
Gross Motor Function Measure (GMFM)
Leiter International Performance Scale (LIPS)
Gross Motor Function Classification System (GMFCS)
Manual Ability Classification System (MACS)
Communication Function Classification System (CFCS)
Eating and Drinking Ability Classification System (EDACS)
• Survival
Exploratory endpoints include
• The relationship between guanabenz PK and safety/efficacy-related biomarkers, such as blood pressure, heart rate and MRI-based quantitative (continuous) markers of change in brain white matter integrity, in an exploratory PK/PD analysis.
• Exploratory search for biomarkers in blood and cerebrospinal fluid. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,5 years after FPI and end of study (approximately 4 years) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker studies in blood and cerebrospinal fluid. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |