Dimethyl Fumarate in Adrenomyeloneuropathy

NCT ID: NCT06513533

Last Updated: 2024-07-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-04-23
• Study Completion Date: 2028-06-30

Brief Summary

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.

Detailed Description

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.

Conditions

Adrenomyeloneuropathy Without Cerebral Involvement

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

DMF arm

Oral administration of dimethyl fumarate, 480 mg/day, for 36 months

Group Type: EXPERIMENTAL

Dimethyl fumarate

Intervention Type: DRUG

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

Placebo arm

Oral administration of placebo for 24 months, followed by oral dimethyl fumarate, 480 mg/day for 12 months

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

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

Interventions

Placebo

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

Intervention Type: OTHER

Dimethyl fumarate

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

Intervention Type: DRUG

Other Intervention Names

Skilarence; Tecfidera

Eligibility Criteria

Inclusion Criteria

• Men and women of 18 to 65 years old at the time of the inclusion, suffering from AMN with:

• elevated plasma VLCFA
• ABCD1 gene mutation identified
• Clinical signs of AMN with at least pyramidal signs in the lower limbs and difficulties to walk (EDSS score ≥ 2.0 and ≤ 6.5). EDSS score will also be re-evaluated at M12, M24 and M36.
• Normal brain MRI or brain MRI showing:

• abnormalities that can be observed in AMN patients without cerebral demyelination with a maximum Loes score of 4
• and/or stable (≥ 6 months) cerebral demyelination without gadolinium enhancement with a Loes score ≤ 12
• Appropriate steroid replacement if adrenal insufficiency is present
• Potential childbearing women should use an adequate method of contraception to avoid pregnancy throughout the study to minimize the risk of pregnancy. If oral contraceptives are used, the use of an alternative barrier method is recommended.
• Likely to be able to participate in all scheduled evaluations and complete all required study procedures
• Signed and dated written informed consent to participate in the study in accordance with local regulations

Exclusion Criteria

• Any progressive neurological disease other than AMN
• Leukopenia below 3.0x109/L, lymphopenia below 0.5x109/L or other pathological results in the complete blood count
• Suspected or confirmed progressive multifocal leukoencephalopathy (PML)
• Severe gastrointestinal disease
• Uncontrolled hepatic, renal or cardiovascular disease, or any evolutive malignancy
• Pregnancy and breast-feeding in woman and potential childbearing woman unable or unwilling to use an acceptable contraceptive method during the study
• Any new medication for AMN initiated less than three months prior to inclusion
• Contra-indications for MRI procedure such as subjects with paramagnetic materials in the body as aneurysm clips, pacemakers, intraocular metal or cochlear implants
• Inclusion in another therapeutic clinical trial for ALD
• Not easily contactable by the investigator in case of emergency or not able to call the investigator

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Instituto de Salud Carlos III

OTHER_GOV

Sponsor Role: collaborator

Spanish Clinical Research Network - SCReN

NETWORK

Sponsor Role: collaborator

Institut d'Investigació Biomèdica de Bellvitge

OTHER

Sponsor Role: collaborator

Pujol, Aurora, M.D.

INDIV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carlos Casasnovas, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Bellvitge University Hospital

Locations

Bellvitge University Hospital

L'Hospitalet de Llobregat, Barcelona, Spain

Site Status: RECRUITING

Donostia University Hospital

Donostia / San Sebastian, , Spain

Site Status: NOT_YET_RECRUITING

University Hospital 12 de Octubre

Madrid, , Spain

Site Status: RECRUITING

Countries

Spain

Central Contacts

Aurora Pujol, MD, PhD

Role: CONTACT

apujol@idibell.cat

+34936073800 ext. 7135

Stéphane Fourcade, PhD

Role: CONTACT

sfourcade@idibell.cat

+34936073800 ext. 3332

Facility Contacts

Carlos Casasnovas, MD, PhD

Role: primary

carloscasasnovas@bellvitgehospital.cat

+34932607711

Adolfo López de Munain, MD, PhD

Role: primary

adolfojose.lopezdemunainarregui@osakidetza.eus

+34943006294

Montserrat Morales, MD

Role: primary

montserrat.morales@salud.madrid.org

+34913908247

Other Identifiers

2021-003826-65

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

XAMNDMFAP2022

Identifier Type: -

Identifier Source: org_study_id