Effect of dimethyl fumarate administered to patients with adrenomyeloneuropathy: a multicenter, placebo controlled, phase IIb/III trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacio Institut D Investigacio Biomedica De Bellvitge IDIBELL

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

15 Apr 2024 → ongoing

Decision date (initial)

2024-01-31

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of the trial is to demonstrate the superiority of DMF at 480 mg/day over placebo in the clinical improvement of patients with AMN.

Secondary objectives 1

1. The secondary objective of the trial is the assessment of safety of DMF in AMN patients.

Conditions and MedDRA coding

Adrenomyeloneuropathy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 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
2. 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.
3. 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
4. Appropriate steroid replacement if adrenal insufficiency is present
5. 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.
6. Likely to be able to participate in all scheduled evaluations and complete all required study procedures
7. Signed and dated written informed consent to participate in the study in accordance with local regulations

Exclusion criteria 10

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the mean change in 2 Minute Walk Test (2MWT) between M0 and M24. This criterion will also be evaluated at M6, M12 and at the end of the extension phase (M36). Details about the 2MWT are given in chapter 3.7.

Secondary endpoints 12

1. Secondary efficacy endpoints will be evaluated by the 6 Minute Walk Test (6MWT), the Time to walk 25 feet (TW25), the Postural Sway, the stair-climbing test, the strength, one questionnaire about urinary tract function (SF-Qualiveen), one questionnaire to assess fecal incontinence (RFIS), neuroimaging and biological markers. Details are given in chapter 3.7.
2. Mean changes in 6MWT, TW25 between M0 and M24. Evaluation will also be done at M6, M12 and M36.
3. Mean changes in postural sway, stair-climbing test, and strength between M-1 and M24. Evaluation will also be done at M12 and M36.
4. Mean changes in the SF-Qualiveen and RFIS between M0 and M24. Evaluation will also be done at M12 and M36.
5. Mean changes in Loes score, diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) parameters in the cerebral white matter on M-1 and M24. Evaluation will also be done at M12 and M36.
6. Mean changes in markers of target-engagement (oxidative damage and inflammation) between M-1 and M24. Evaluation will also be done at M3 and M12.
7. Markers of neuroaxonal damage and astrocyte activation: • Mean changes in NfL and GFAP in plasma at M-1, M3, M12, and M24, and in CSF at M0 and M24.
8. Very long-chain fatty acid (VLCFA) levels • Mean changes in C26:0 and C24:0 in plasma and CSF at M-1, and M24.
9. Single cell RNA sequencing (scRNAseq) of PBMC • Comparison of scRNAseq data from n=5 AMN patients (group 1: placebo), and n=10 from AMN (group 2: DMF), plus 10 samples from of age and sex-matched control adults at M-1 and M3.
10. Lipidomics • Analysis of glycerolipids, glycerophospholipids, and sphingolipids at M-1, M3, M12 and M24 in plasma.
11. Metabolomics • Analysis of metabolomics in stools at M-1, and M6.
12. Metagenomics • Identification in stools of the different taxa, and enzymes affected by the treatment with DMF at M-1 and M6.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacio Institut D Investigacio Biomedica De Bellvitge IDIBELL

Sponsor organisation

Fundacio Institut D Investigacio Biomedica De Bellvitge IDIBELL

Address

Avinguda De La Gran Via De L'hospitalet 199

City

L'hospitalet De Llobregat

Postcode

08908

Country

Spain

Scientific contact point

Organisation

Fundacio Institut D Investigacio Biomedica De Bellvitge IDIBELL

Contact name

Montserrat Ruiz Sales

Public contact point

Organisation

Fundacio Institut D Investigacio Biomedica De Bellvitge IDIBELL

Contact name

Montserrat Ruiz Sales

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications