A Clinical Trial for AMN: Validation of Biomarkers of Oxidative Stress, Efficacy and Safety of a Mixture of Antioxidants

A Clinical Trial for Adrenomyeloneuropathy (AMN): Validation of Biomarkers of Oxidative Stress, and Efficacy, Tolerance and Safety of a Mixture of the Antioxidants N-acetylcysteine, Lipoic Acid and Vitamin E

X-linked adrenoleukodystrophy is a rare, demyelinating and neurodegenerative disorder, due to a loss of function of a fatty acid transporter, the peroxisomal ABCD1protein. Its more frequent phenotype, the adrenomyeloneuropathy in adults, is characterized by axonal degeneration in spinal cord, spastic paraparesis and a disabling peripheral neuropathy. Actually, there is no efficient treatment for the disease. Our work in the last twelve years dissecting the physiopathological basis of the disorder has uncovered an involvement of the oxidative stress early in the neurodegenerative cascade. In a preclinical trial we have identified an antioxidant cocktail that efficiently reverse the clinical symptoms and the axonal degeneration in the mouse model for the disease. We propose the translation of the results to an open trial to test the tolerance and effectiveness of these drugs in the correction of the previously identified oxidative lesion biomarkers, as a first step to a randomized versus placebo, multicentric and international trial. You will be clinically explored and assessed in the Hospital Universitari of Bellvitge (HUB) using clinical scales for spasticity, disability, electroneurogram and cranial and spinal Nuclear Magnetic resonance (NMR). The information will be collected in a data base that will be of great value to improve the present attention and the future follow-up to facilitate your inclusion in therapeutic randomized, double blind, against placebo clinical trials.

Study Overview

• Status: Completed
• Conditions: Adrenomyeloneuropathy
• Intervention / Treatment: Drug: N-acetylcysteine; Drug: lipoic acid; Drug: vitamin E

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona
    • L'Hospitalet de LLobregat, Barcelona, Spain, 08907
      • Hospital Universitari de Bellvitge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Symptomatic AMN patients,
• 18-64 years old,
• male and female,
• clinically and biochemically diagnosed;
• females must be obligated heterozygotes or must have gene mutation identified.

Exclusion Criteria:

• Pregnant and lactation in females,
• Cerebral inflammatory disease with cognitive disorder, and/or
• need the help of two walking sticks,
• epilepsy,
• hypersensibility to cysteine related compounds,
• transaminases 2 fold up normal values.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N-acetylcysteine, lipoic acid and vitamin E; Two Dose titration design	Drug: N-acetylcysteine; N-acetylcysteine, 800-2400 mg daily for 2 months; Drug: lipoic acid; lipoic acid, 300-600 mg daily for 2 months; Drug: vitamin E; vitamin E, 150-300 mg daily for 2 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
oxidative lesion biomarkers	oxidative lesion biomarkers: protein, DNA and peroxidation biomarkers	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical parameters	spasticity, disability,electroneurograms and evocated potentials. Cranial and spinal NMR will be done at the beginning and the end of the trial.	2, 6 and 12 months

Collaborators and Investigators

• Sponsor: Onofre, Aurora Pujol, M.D.
• Collaborators: Ministerio de Sanidad, Servicios Sociales e Igualdad; Fundacion Hesperia

Publications and helpful links

General Publications

• Lopez-Erauskin J, Fourcade S, Galino J, Ruiz M, Schluter A, Naudi A, Jove M, Portero-Otin M, Pamplona R, Ferrer I, Pujol A. Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy. Ann Neurol. 2011 Jul;70(1):84-92. doi: 10.1002/ana.22363.
• Galino J, Ruiz M, Fourcade S, Schluter A, Lopez-Erauskin J, Guilera C, Jove M, Naudi A, Garcia-Arumi E, Andreu AL, Starkov AA, Pamplona R, Ferrer I, Portero-Otin M, Pujol A. Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-adrenoleukodystrophy. Antioxid Redox Signal. 2011 Oct 15;15(8):2095-107. doi: 10.1089/ars.2010.3877. Epub 2011 Jun 8.
• Parameswaran J, Goicoechea L, Planas-Serra L, Pastor A, Ruiz M, Calingasan NY, Guilera C, Aso E, Boada J, Pamplona R, Portero-Otin M, de la Torre R, Ferrer I, Casasnovas C, Pujol A, Fourcade S. Activating cannabinoid receptor 2 preserves axonal health through GSK-3beta/NRF2 axis in adrenoleukodystrophy. Acta Neuropathol. 2022 Aug;144(2):241-258. doi: 10.1007/s00401-022-02451-2. Epub 2022 Jul 1.
• Casasnovas C, Ruiz M, Schluter A, Naudi A, Fourcade S, Veciana M, Castaner S, Alberti A, Bargallo N, Johnson M, Raymond GV, Fatemi A, Moser AB, Villarroya F, Portero-Otin M, Artuch R, Pamplona R, Pujol A. Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study. Neurotherapeutics. 2019 Oct;16(4):1167-1182. doi: 10.1007/s13311-019-00735-2.

Helpful Links

• The Neurometabolic Diseases Lab, led by ICREA Research Professor Aurora Pujol, is integrated in the Neurosciences Area of IDIBELL.
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Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: November 28, 2011
• First Submitted That Met QC Criteria: December 16, 2011
• First Posted (Estimate): December 19, 2011

Study Record Updates

• Last Update Posted (Actual): March 11, 2019
• Last Update Submitted That Met QC Criteria: March 7, 2019
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: AMN; XALD
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Leukoencephalopathies; Adrenal Gland Diseases; Hereditary Central Nervous System Demyelinating Diseases; Peroxisomal Disorders; Adrenal Insufficiency; Adrenoleukodystrophy; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Micronutrients; Respiratory System Agents; Vitamins; Antioxidants; Antidotes; Vitamin B Complex; Free Radical Scavengers; Expectorants; Vitamin E; Acetylcysteine; N-monoacetylcystine; Thioctic Acid
• Other Study ID Numbers: XAMNANTIOXAP2010