Intracerebral Gene Therapy for MLD

• Register: EUCTR
• Last refreshed on: 19 May 2014
• Main ID: EUCTR2011-004410-42-FR
• Date of registration: 19/12/2012
• Prospective Registration: No
• Primary sponsor: Inserm
• Public title: Intracerebral Gene Therapy for MLD
• Scientific 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 - Intracerebral Gene Therapy for MLD
• Date of first enrolment: 26/11/2012
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-004410-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no

Countries of recruitment

France

Contacts

• Name: Anne PUECH
• Affiliation: Inserm

• Name: Anne PUECH
• Affiliation: Inserm

Key inclusion & exclusion criteria

Inclusion criteria:
- Boys or girls with an ealry onset form of MLD
- Age between 6 months ans 4 years, inclusive
- Interval between age of first symptoms and age of inclusion muyst be 12 or less months
- 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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 5
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 > 10mm in the frontal region.
-MLD MRI severity score >14
- Performance IQ<70 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 dysfuncion
- 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 impossibilty
- Evoked potential impossibility
- Participation to another therapeutic clinical trial for MLD
- Unaffiliated to any French health insurance or any other European National Health Insurance


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Early onset forms of MLD
MedDRA version: 14.1 Level: SOC Classification code 10029205 Term: Nervous system disorders System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 14.1 Level: PT Classification code 10067609 Term: Metachromatic leukodystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders
MedDRA version: 14.1 Level: SOC Classification code 10027433 Term: Metabolism and nutrition disorders System Organ Class: 10027433 - Metabolism and nutrition disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: AAVrh.10cuARSA
Product Code: Non applicable
Pharmaceutical Form: Solution for injection

Primary Outcome(s)

Main Objective: The primary goal of the trial is the assessment of tolerance (safety) of the intracerebral adminsitration of a single dose of AAVrh.10cuARSA

Primary end point(s): A) SAFETY
Early follow-up: safety or neurosurgical procedure (M0-M1)
- Standard clinical and neurological exam and monitoring of adverse events associated to the procedure
- Standard laboratory tests
- CT scan
- Brain MRI
Follow-up after the neurosurgical procedure (M1-M24)
- Standard clinical and laboratory tests and adverse event monitoring
- Brain MRI

B) Primary efficacy endpoint
MLD neurological severity score

Secondary Objective: Evaluate the efficacy of intracerebral administration of a single dose of a AAVrh.210cuARSA to stop the disease progression

Timepoint(s) of evaluation of this end point: A) SAFETY
Early follow-up: safety or neurosurgical procedure (M0-M1)
- Standard clinical and neurological exam and monitoring of adverse events associated to the procedure: day +1, +3, +7, +10 and months +1
- Standard laboratory tests: day +3, +10, and months +1
- CT scan: within 36 hours of the procedure
- Brain MRI day +6 and month +1
Follow-up after the neurosurgical procedure (M1-M24)
- Standard clinical and laboratory tests and adverse event monitoring months 1,3,6,9,15 18 and 24
- Brain MRI months +3, +9, +15 and +24

B) Primary efficacy endpoint
MLD neurological severity score at months +1, +3, +6, +12 +18 and +24

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Motor scores (GMFM, Ashworth and ICARS): at months +1, +3 for GMFM ans Ahshworth tests only, and +6, +12, +18and +24 for all tests
Neurological evaluation at each visit.
Cognitive functions (Bayey Scales of Infant Development at months +3, +9, +15 and +24.
MLD severity MRI score, MRI-DTI parameters, measurement of cerebral atrophy and spectroscopy at months +1, +3, +6, +9, +15 and +24.
Neuroelectrophysiological tests (peripheral nerve condution velocity, visual, auditory at months +3, 15 and +24 and somatosensory evoked potentials)

Secondary end point(s): Motor scores (GMFM, Ashworth and ICARS)
Neurological evaluation
Cognitive functions (Bayey Scales of Infant Development
MLD severity MRI score, MRI-DTI parameters, measurement of cerebral atrophy and spectroscopy
Neuroelectrophysiological tests (peripheral nerve condution velocity, visual, auditory and somatosensory evoked potentials)

Secondary ID(s)

C11-09

Source(s) of Monetary Support

French ministry of research: PHRC (hospital program for clinical research)