Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy (TG-MLD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Institut National de la Santé Et de la Recherche Médicale, France
Sponsor:
Collaborators:
European Leukodystrophy Association
Assistance Publique - Hôpitaux de Paris
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier:
NCT01801709
First received: January 28, 2013
Last updated: January 28, 2014
Last verified: January 2014
  Purpose

The objective of this open-label, single arm, monocentric, phase I/II clinical study is to assess safety and efficacy of ARSA gene transfer in the brain of children affected with early onset forms of Metachromatic Leukodystrophy (MLD). For this purpose, an adeno-associated virus serotype rh.10 (AAVrh.10) vector will be used to transfer the ARSA cDNA coding for Arylsulfatase A (ARSA) enzyme into the brain of children. Five patients with early onset form of MLD, age ranging from 6 months to 4 years, will be included in this protocol and will be followed during 24 months.

Patients will be selected at presymptomatic or early stage of their disease, following clinical, neuropsychological and brain imaging criteria.

Twelve simultaneous injections of the investigational medicinal product will be performed in the white matter of both brain hemispheres, through 6 image-guided tracks, with 2 deposits per track.

A low dose (1x10EXP12 vg total) will be administered to the first 2 patients, while the last 3 will receive a higher dose (4x10EXP12 vg total).

Safety and efficiency will be evaluated based on clinical, neuropsychological, radiological, electrophysiological and biological parameters.


Condition Intervention Phase
Metachromatic Leukodystrophy
Genetic: intracerebral administration of AAVrh.10cuARSA
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II, Open Labeled, Monocentric Study of Direct Intracranial Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human ARSA cDNA to Children With Metachromatic Leukodystrophy.

Resource links provided by NLM:


Further study details as provided by Institut National de la Santé Et de la Recherche Médicale, France:

Primary Outcome Measures:
  • Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA [ Time Frame: During the two years follow-up ] [ Designated as safety issue: Yes ]

    Tolerance will be measured by :

    • Adverse event,
    • Clinical and neurological exams,
    • Laboratory tests,
    • Neuroimagery (CT scan, brain MRI).


Secondary Outcome Measures:
  • Evaluate the efficacy of intracerebral administration of a single dose of AAVrh.10cuARSA to stop the disease progression. [ Time Frame: During the two years follow-up ] [ Designated as safety issue: No ]

    Efficacy will be measured by:

    • MLD neurological severity score,
    • Neurological evaluation,
    • Motor scores (GMFM, Ashworth and ICARS),
    • Cognitive functions (Bayley Scales of Infant Development (BSID)(0-42 months), or Wechsler Preschool and Primary Scale of Intelligence-III (WPPSI-III) (43 months-6 years)),
    • MLD severity MRI score, MRI-DTI parameters, measurement of cerebral atrophy and spectroscopy,
    • Neuroelectrophysiological tests (peripheral nerve conduction velocity, visual, auditory and somatosensory evoked potentials).


Estimated Enrollment: 5
Study Start Date: March 2013
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AAVrh.10cuARSA
intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres.
Genetic: intracerebral administration of AAVrh.10cuARSA

  Eligibility

Ages Eligible for Study:   6 Months to 5 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Boys or girls with an early onset form of MLD.
  • Age between 6 months and 5 years, inclusive
  • Diagnostic of MLD based on the measurement of ARSA activity in leukocytes and the accumulation of sulfatides in urine, along with normal activity of at least one other sulfatase
  • Informed consent signed up and willingness for monitoring 2 years after treatment.
  • Normal values for standard laboratory tests

Exclusion Criteria:

  • Absence of ARSA protein by immunocytochemistry and/or ELISA
  • Gestational age <32 weeks of amenorrhoea and age < 1 year
  • Brain atrophy with a subdural space > 10 mm in the frontal region
  • Performance IQ<50 at WPPSI-III or cognitive function < 3rd percentile at the Bayley's test of infant development
  • If age > 16 months at inclusion, inability to walk few steps alone OR inability to walk few steps with support on one side along with inability to stand up alone
  • Impossibility for anesthesia
  • Malignancy, cardiac malformation, liver dysfunction, or renal dysfunction
  • Neurological disorder, except benign, not related to MLD.
  • Any other clinically significant untreated co-morbid medical condition as determined by the clinical investigator, including cardiac, pulmonary or kidney disease.
  • MRI impossibility
  • Evoked potential impossibility
  • Participation to another therapeutic clinical trial for MLD.
  • Unaffiliated to any French or any other National Health Insurance.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01801709

Contacts
Contact: Patrick Aubourg, MD - PhD 33.1 4959 5396 patrick.aubourg@inserm.fr
Contact: Caroline Sevin, MD - PhD 33.1 4521 3017 caroline.sevin@inserm.fr

Locations
France
Bicêtre Hospital - Paris Sud Recruiting
Le Kremlin-Bicêtre, France
Contact: Patrick Aubourg       patrick.aubourg@inserm.fr   
Contact: Caroline Sevin       caroline.sevin@inserm.fr   
Principal Investigator: Patrick Aubourg         
Principal Investigator: Caroline Sevin         
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
European Leukodystrophy Association
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Patrick Aubourg, MD-PhD Assistance Publique - Hôpitaux de Paris and Institut National de la Santé et de la Recherche Médicale
Study Director: Caroline Sevin, MD-PhD Assistance Publique - Hôpitaux de Paris
Study Director: Michel Zerah, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Thomas Roujeau, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Nathalie Cartier, MD, PhD Institut National de la Santé et de la Recherche Biomédicale
  More Information

Publications:
Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT01801709     History of Changes
Other Study ID Numbers: C11-09, 2011-004410-42
Study First Received: January 28, 2013
Last Updated: January 28, 2014
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
Brain Gene Therapy
Adeno Associated vector
Lysosomal sotage diseases
Leukodystrophies

Additional relevant MeSH terms:
Leukodystrophy, Metachromatic
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Demyelinating Diseases
Genetic Diseases, Inborn
Hereditary Central Nervous System Demyelinating Diseases
Leukoencephalopathies
Lipid Metabolism Disorders
Lipid Metabolism, Inborn Errors
Lipidoses
Lysosomal Storage Diseases
Lysosomal Storage Diseases, Nervous System
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases
Sphingolipidoses
Sulfatidosis

ClinicalTrials.gov processed this record on October 22, 2014