The goal of this clinical trial is to determine if dimethyl fumarate is effective in treating motor problems in adults with Adrenomyeloneuropathy. The trial will also assess the safety of dimethyl fumarate and explore the molecular mechanisms underlying the disease. The primary questions it aims to answer are: * Does dimethyl fumarate improve motor problems in participants? * What medical issues do participants experience while taking dimethyl fumarate? Researchers will compare the effects of dimethyl fumarate to a placebo (a substance that looks like the drug but contains no active ingredients) to evaluate its effectiveness in treating Adrenomyeloneuropathy. Participants will: * Take either dimethyl fumarate or a placebo daily for 36 months. * Visit the clinic at the start of the trial, then at 3 months, 6 months, and every 6 months thereafter for checkups and tests.
Adrenoleukodystrophy (X-ALD) is the most prevalent rare genetic disorder affecting the brain's white matter. It is caused by mutations in the ABCD1 gene, which encodes a transporter involved in the degradation of very long-chain fatty acids (VLCFA). As a result, VLCFA accumulate in tissues and plasma, serving as a pathognomonic biomarker for diagnosis. The disease manifests in two main forms: i) adrenomyeloneuropathy (AMN), characterized by chronic progressive spastic paraplegia due to distal axonopathy, and ii) cerebral ALD (cALD), a rapidly progressing and fatal demyelinating leukodystrophy. Current therapeutic options are inadequate, limited to bone marrow transplants and gene therapy for patients with cerebral inflammation. No treatment is available for AMN, which affects 60% of patients. We have discovered that excess VLCFA leads to mitochondrial reactive oxygen species (ROS) production and oxidative damage, a major factor driving pathogenesis. More recently, we found that the main endogenous response to oxidative damage (the NRF-2 pathway) is impaired in X-ALD. Preclinical tests with an NRF2 activator, specifically the current treatment for multiple sclerosis, dimethyl fumarate (DMF/Tecfidera), showed promising results. All major molecular and cellular pathogenic mechanisms were restored, including: i) mitochondrial function and biogenesis, ii) redox homeostasis, iii) bioenergetic failure, iv) neuroinflammation, along with axonal damage and clinical signs of the disease such as locomotor disability. Consequently, we obtained an international patent for repurposing DMF for X-ALD (US15/957,601) and Orphan Drug Designation by the EMA in 2020 (EMA/OD/0000010028). Now we are translating this knowledge into a randomized phase IIb/III double-blind placebo-controlled study over 36 months for 40 AMN patients, to determine if DMF is effective in these patients. For the first 24 months, patients will be divided into two groups (placebo and active treatment) in a ratio of 1:2. A 12-month extension phase will follow, during which all patients will receive treatment. Furthermore, we aim to elucidate the molecular mechanisms driving the disease and dissect the redox-inflammatory effects of DMF using an integrative multi-omics approach, which will involve single-cell RNA sequencing in PBMC, and lipidomics in plasma. The clinical and molecular data from historical national and international AMN and cALD cohorts will be pooled to identify markers of severity and progression. Our goal is to address unmet needs in AMN while generating novel fundamental knowledge that will be useful for this and other common axonopathies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
40
1 tablet twice daily (one in the morning and one in the evening) for the first 7 days as a starter dose followed by 2 tablets (240 mg) twice daily
1 tablet twice daily (one in the morning and one in the evening) for the first 7 days as a starter dose followed by 2 tablets (240 mg) twice daily
Bellvitge University Hospital
L'Hospitalet de Llobregat, Barcelona, Spain
RECRUITINGDonostia University Hospital
Donostia / San Sebastian, Spain
NOT_YET_RECRUITINGUniversity Hospital 12 de Octubre
Madrid, Spain
RECRUITINGPostural sway test
Balance is assessed with static posturography by measuring the extent of postural sway in four conditions, each for two 20-second trials: (1) eyes open feet shoulder width apart (EOFA), (2) eyes closed feet shoulder width apart (ECFA), (3) eyes open feet together (EOFT), and (4) eyes closed feet together (ECFT)
Time frame: Interim analysis 1 (at 12 months of treatment)
Postural sway test
Balance is assessed with static posturography by measuring the extent of postural sway in four conditions, each for two 20-second trials: (1) eyes open feet shoulder width apart (EOFA), (2) eyes closed feet shoulder width apart (ECFA), (3) eyes open feet together (EOFT), and (4) eyes closed feet together (ECFT)
Time frame: Final analysis 1 (at 24 months of treatment)
Postural sway test
Balance is assessed with static posturography by measuring the extent of postural sway in four conditions, each for two 20-second trials: (1) eyes open feet shoulder width apart (EOFA), (2) eyes closed feet shoulder width apart (ECFA), (3) eyes open feet together (EOFT), and (4) eyes closed feet together (ECFT)
Time frame: Final analysis 2 (at 36 months of treatment)
2 Minute Walk Test (2MWT)
It measures the distance an individual is able to walk over a total of two minutes on a hard, flat surface.
Time frame: Interim analysis 1 (at 6 months of treatment)
2 Minute Walk Test (2MWT)
It measures the distance an individual is able to walk over a total of two minutes on a hard, flat surface.
Time frame: Interim analysis 2 (at 12 months of treatment)
2 Minute Walk Test (2MWT)
It measures the distance an individual is able to walk over a total of two minutes on a hard, flat surface.
Time frame: Final analysis 1 (at 24 months of treatment)
2 Minute Walk Test (2MWT)
It measures the distance an individual is able to walk over a total of two minutes on a hard, flat surface.
Time frame: Final analysis 2 (at 36 months of treatment)
6 Minute Walk Test (6MWT)
It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface
Time frame: Interim analysis 1 (at 6 months of treatment)
6 Minute Walk Test (6MWT)
It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface
Time frame: Interim analysis 2 (at 12 months of treatment)
6 Minute Walk Test (6MWT)
It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface
Time frame: Final analysis 1 (at 24 months of treatment)
6 Minute Walk Test (6MWT)
It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface
Time frame: Final analysis 2 (at 36 months of treatment)
Time to walk 25 Feet (TW25)
The TW25 (time to walk 25 feet) is a widely used outcome measure of Leg function/ambulation
Time frame: Interim analysis 1 (at 6 months of treatment)
Time to walk 25 Feet (TW25)
The TW25 (time to walk 25 feet) is a widely used outcome measure of Leg function/ambulation
Time frame: Interim analysis 2 (at 12 months of treatment)
Time to walk 25 Feet (TW25)
The TW25 (time to walk 25 feet) is a widely used outcome measure of Leg function/ambulation
Time frame: Final analysis 1 (at 24 months of treatment)
Time to walk 25 Feet (TW25)
The TW25 (time to walk 25 feet) is a widely used outcome measure of Leg function/ambulation
Time frame: Final analysis 2 (at 36 months of treatment)
Stair-climbing
Participants are timed using a hand-held stopwatch as they ascended one flight of 4 steps as quickly and safely as possible with handrail use allowed as needed
Time frame: Interim analysis 1 (at 12 months of treatment)
Stair-climbing
Participants are timed using a hand-held stopwatch as they ascended one flight of 4 steps as quickly and safely as possible with handrail use allowed as needed
Time frame: Final analysis 1 (at 24 months of treatment)
Stair-climbing
Participants are timed using a hand-held stopwatch as they ascended one flight of 4 steps as quickly and safely as possible with handrail use allowed as needed
Time frame: Final analysis 2 (at 36 months of treatment)
Strength
The average of two maximal effort break test trials for each side and muscle group is measured using a dynamometer and documented in Kg
Time frame: Interim analysis 1 (at 12 months of treatment)
Strength
The average of two maximal effort break test trials for each side and muscle group is measured using a dynamometer and documented in Kg
Time frame: Final analysis 1 (at 24 months of treatment)
Strength
The average of two maximal effort break test trials for each side and muscle group is measured using a dynamometer and documented in Kg
Time frame: Final analysis 2 (at 36 months of treatment)
SF-Qualiveen (Short-Form Qualiveen)
The Qualiveen is a specific patients' health-related quality of life developed to assess the impact of urinary disorders in patients with neurological conditions.
Time frame: Interim analysis 1 (at 12 months of treatment)
SF-Qualiveen (Short-Form Qualiveen)
The Qualiveen is a specific patients' health-related quality of life developed to assess the impact of urinary disorders in patients with neurological conditions.
Time frame: Final analysis 1 (at 24 months of treatment)
SF-Qualiveen (Short-Form Qualiveen)
The Qualiveen is a specific patients' health-related quality of life developed to assess the impact of urinary disorders in patients with neurological conditions.
Time frame: Final analysis 2 (at 36 months of treatment)
Revised Fecal Incontinence Scale (RFIS)
The RFIS is a short, reliable, and valid five item scale that can be used to assess fecal incontinence and to monitor patient outcomes following treatment.
Time frame: Interim analysis 1 (at 12 months of treatment)
Revised Fecal Incontinence Scale (RFIS)
The RFIS is a short, reliable, and valid five item scale that can be used to assess fecal incontinence and to monitor patient outcomes following treatment.
Time frame: Final analysis 1 (at 24 months of treatment)
Revised Fecal Incontinence Scale (RFIS)
The RFIS is a short, reliable, and valid five item scale that can be used to assess fecal incontinence and to monitor patient outcomes following treatment.
Time frame: Final analysis 2 (at 36 months of treatment)
Brain neuroimaging: Loes
The Loes score is a 34-point imaging-based severity scale-based scoring system for patients with X-ALD based on the neuroanatomical involvement and the presence or absence of total and/or global atrophy. This 34-point imaging-based severity scale was based on the location and extent of central nervous system involvement and presence of either focal or global atrophy.
Time frame: Interim analysis 1 (at 12 months of treatment)
Brain neuroimaging: Loes
The Loes score is a 34-point imaging-based severity scale-based scoring system for patients with X-ALD based on the neuroanatomical involvement and the presence or absence of total and/or global atrophy. This 34-point imaging-based severity scale was based on the location and extent of central nervous system involvement and presence of either focal or global atrophy.
Time frame: Final analysis 1 (at 24 months of treatment)
Brain neuroimaging: Loes
The Loes score is a 34-point imaging-based severity scale-based scoring system for patients with X-ALD based on the neuroanatomical involvement and the presence or absence of total and/or global atrophy. This 34-point imaging-based severity scale was based on the location and extent of central nervous system involvement and presence of either focal or global atrophy.
Time frame: Final analysis 2 (at 36 months of treatment)
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