Table 1 Protocol overview

Current age

 ≥ 18 years

 ≥ 6—< 18 years

 < 6 years

Design

Double-blind randomized placebo-controlled trial

Open-label trial

Inclusion criteria

Males and females ≥ 18 y of age at screening, with a confirmed diagnosis of neurologically symptomatic VWM^a

Males and females ≥ 6—< 18 y of age at screening, with a confirmed diagnosis of neurologically symptomatic VWM^a

Males and females < 6 y of age at screening, with a confirmed diagnosis of neurologically symptomatic VWM^a

1. WAIS IV: perceptual reasoning index (based on block design, visual puzzles and matrix reasoning) ≥ 50

1. WISC V: visuospatial reasoning (based on block design and visual puzzles) OR fluid reasoning (based on matrix reasoning and figure weights) ≥ 50

1. HUI generic score > 0

2. Can walk ≥ 10 steps without support or with light support of both hands (must meet GMFM-88, item 67)

3. Being stable^b

Exclusion criteria

1. Comorbidity with any relevant disease or condition that would impair assessment of disease progression or of treatment effect, based on clinical judgement of an expert in VWM

2. Unable to undergo MRI due to metal-containing implants, such as cochlea implant, neurostimulator or pacemaker

3. Simultaneous participation in another interventional trial

4. Unable or unwilling to comply with all details of the protocol

5. Situation in which adherence to the study medication or follow-up procedures cannot be guaranteed

6. Known allergy or hypersensitivity to the investigational treatment or to any of the other components of the formulation used in this study

Study schedule

• The treatment period is 2 years

• All clinical assessments and body fluid biomarkers are assessed at least at 0, 3, 6, 12, 18 and 24 months; MRI and neuropsychological testing at 0, 12 and 24 months

• An open-label extension with annual assessments is recommended until the last included patient has been followed for 2 years. At the end of the overall study, all patients will undergo a final assessment if the previous assessment was ≥ 6 months ago

• After the trial, all patients should have access to open-label extension, pending review and approval of the DSMB

Common endpoints

Clinical endpoints

• Health Utilities index 3 [43, 44], including the self-care item of the HUI2, as described [1]

• Vineland Adaptive Behavior Scales, 3^rd edition (Vineland-3)

• Leiter International Performance Scale (LIPS)—third edition [45]

• Gross Motor Function Measure (GMFM-88) [46]

• Gross motor function classification in MLD (GMFC-MLD) [47]

• Expressive language function classification – MLD (ELFC-MLD) [48]

• Manual ability classification system (MACS) [49]

• Euro-Quality of Life Instrument 5D, 5 levels (EQ-5D-5L) [50]

• Pediatric Quality of Life Inventory (PedsQL) [51, 52]

• Clinical Global Impression-Severity (CGI-S) [40]

• Caregiver Global Impression-Severity (CaGI-S) [40]

Quantitative brain MRI parameters

• 3D T1-weighted and 3D FLAIR imaging, allowing segmentation into normal cerebral white matter, abnormal cerebral white matter (FLAIR hyperintense), rarefied and cystic cerebral white matter (FLAIR hypointense) and CSF [4]

• T2-weighted axial imaging

• Diffusion Tensor Imaging (DTI)

Biomarkers in body fluids

• Serum neurofilament light chain

Health economic evaluation

• Medical Consumption Questionnaire (iMCQ) [53]

• Productivity Cost Questionnaire (iPCQ) [54]

Adverse events and serious adverse events

Adverse events and serious adverse events are 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), as well as applying a scale to grade the impact of adverse events on daily life

Safety

Each sponsor defines its safety assessments, to be discussed with the VWM consortium. Long-term safety assessment is part of the post-authorization registry-based studies and includes monitoring for increased risks of cancer and potential consequences of a failed stress response

Age- specific endpoints

• 10 m walk test [55]

• 9 hole peg test [39]

• Columbia-Suicide Severity Rating Scale (C-SSRS) [41]

• WAIS IV: perceptual reasoning index (based on block design, visual puzzles and matrix reasoning) ≥ 50

• Montreal Cognitive Assessment (MoCA) 8.1 (executive function, memory, attention, word fluency, orientation, and visuo-constructive function) [56]

• WISC V: visuospatial reasoning (based on block design and visual puzzles) OR fluid reasoning (based on matrix reasoning and figure weights) ≥ 50