This site became the new ClinicalTrials.gov on June 19th. Learn more.
Show more
ClinicalTrials.gov Menu IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu IMPORTANT: Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu
Give us feedback

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

This study is ongoing, but not recruiting participants.
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: July 20, 2017
Last verified: June 2017
  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: Intervention Model: Single Group Assignment
Masking: None (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 ]

    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 ]

    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 2019
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   (Child)
Sexes Eligible for Study:   All
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

Locations
France
Bicêtre Hospital - Paris Sud
Le Kremlin-Bicêtre, France
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:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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 ( EudraCT Number )
Study First Received: January 28, 2013
Last Updated: July 20, 2017

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
Hereditary Central Nervous System Demyelinating Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sulfatidosis
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Leukoencephalopathies
Demyelinating Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders

ClinicalTrials.gov processed this record on August 18, 2017