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Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00151216
Recruitment Status : Active, not recruiting
First Posted : September 8, 2005
Last Update Posted : April 18, 2019
Sponsor:
Collaborator:
Nathan's Battle Foundation
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Tracking Information
First Submitted Date  ICMJE September 6, 2005
First Posted Date  ICMJE September 8, 2005
Last Update Posted Date April 18, 2019
Study Start Date  ICMJE June 2004
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 9, 2017)
Neurological assessment using the LINCL clinical rating scale [ Time Frame: screening; pre-therapy; and 6 and 18 months post-vector administration ]
The neurological examination will be carried out using a standard format with input from the parents/legal guardians as relevant. The clinical rating scale, referred to as a "CNS disability scale" is made up of individual sum of 4 point scales for each of 3 activities; the ratings for each activity are summed, giving a "CNS disability score". Each of the activities are rated 0 to 3, where 0 is the most severe form of the disease. This scale, developed by Steinfeld et al, originally included the four major functional problems in LINCL (loss of motor performance, seizure activity, loss of vision, and loss of language). In this modified clinical rating system, these are now 3 categories.
Original Primary Outcome Measures  ICMJE
 (submitted: September 6, 2005)
The primary endpoint for the trial is neurological assessment using the LINCL clinical rating scale at screening; pre-therapy; and 6 and 18 months post-vector administration.
Change History Complete list of historical versions of study NCT00151216 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2017)
MRI/MRS assessment [ Time Frame: screening; pre-therapy; and 6 and 18 months post-vector administration ]
The secondary endpoint variable will be the MRI/MRS assessment of the CNS in regions of vector administration. Anatomical measurements of brain parenchymal volume will be combined with proton spectroscopic imaging of the n-acetyl-aspartate (NAA) resonance, a neuronal marker measurable using clinical magnetic resonance techniques.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 6, 2005)
The secondary endpoint variable will be the MRI/MRS assessment of the CNS in regions of vector administration. This will be assessed at screening; pre-therapy; and 6 and 18 months post-vector administration.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis
Official Title  ICMJE Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Expressing the Human CLN2 cDNA to the Brain of Children With Late Infantile Neuronal Ceroid Lipofuscinosis
Brief Summary The aim of this study is to treat the signs and symptoms of late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal inherited disease in the brain. This will be accomplished by using delivery of a gene (method called gene transfer) to administer to the brain an experimental drug called AAV2CUhCLN2, a gene transfer vector.
Detailed Description

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal childhood neurodegenerative lysosomal storage disease with no known therapy. There are estimated to be 200 to 300 children in the USA at any one time with the disease. LINCL is a genetic disease resulting from mutations in the CLN2 gene. The CLN2 gene encodes a protein tripeptidyl peptidase-I (TPP-I) which is absent/deficient in children with LINCL. This absence/deficiency of TPP-I results in lysosomal storage and subsequent cell death (especially neurons). The children with LINCL are chronically ill, with a progressive CNS disorder that invariably results in death, typically by age 8 to 12.

This clinical study will evaluate the concept that persistent expression of the normal CLN2 cDNA in the CNS will result in the production of sufficient amounts of TPP-I to prevent further loss of neurons, and hence limit disease progression. To assess this concept, an adeno-associated virus vector encoding the normal human CLN2 gene (AAV2CUhCLN2) will be used as a vehicle to deliver and express the human CLN2 cDNA in the brain of children with LINCL. The proposed study will include 11 individuals and will be divided into two parts. Group A, to be studied first, will include 5 individuals with the severe form of the disease. Group B of the trial will include 6 individuals with a moderate form of the disease. Following direct intracranial administration of the vector, there will be neurological assessment using the LINCL clinical rating scale and magnetic resonance imaging/magnetic resonance spectroscopy assessment of the CNS in regions of vector administration. The data generated will help evaluate two hypotheses: (1) that it is safe to carry out direct intracranial administration of the AAV2CUhCLN2 vector to the CNS of individuals with LINCL; and (2) that administration of the AAV2CUhCLN2 vector will slow down or halt the progression of the disease in the central nervous system.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
The study will be carried out in two populations of children with LINCL. Group A will include n= 5 children with a total disability score of 0 to 4 (the severe forms of the disease; the staging based on a modification of the scale of Steinfeld et al. Group B will include n=6 children with a total disability score of 5 to 6, a moderate stage of the disease. All of the study population of 11 children (Group A, n= 5 and Group B, n=6) will receive 3x10^12 particle units of the AAV2CUhCLN2 vector divided among 12 locations delivered through 6 burr holes (2 locations at varying depths through each hole), 3 burr holes per hemisphere. The choice of the locations for the burr holes and needle placement will be on a case-by-case basis due to the diffuse and variable nature of the disease presentation.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Batten Disease
  • Late Infantile Neuronal Ceroid Lipofuscinosis
Intervention  ICMJE Biological: AAV2CUhCLN2 (3x10^12 particle units)
gene transfer; one-time administration via neuro surgery procedure
Study Arms  ICMJE
  • Experimental: Group A-Severe Stages of LINCL

    Group A will include n= 5 children with a total disability score of 0 to 4 (the severe forms of the disease; the staging based on a modification of the scale of Steinfeld et al.

    All subjects will receive 3x10^12 particle units of the AAV2CUhCLN2 vector.

    Intervention: Biological: AAV2CUhCLN2 (3x10^12 particle units)
  • Experimental: Group B-Moderate Stages of LINCL

    Group B will include n=6 children with a total disability score of 5 to 6, a moderate stage of the disease.

    All subjects will receive 3x10^12 particle units of the AAV2CUhCLN2 vector.

    Intervention: Biological: AAV2CUhCLN2 (3x10^12 particle units)
Publications * Worgall S, Sondhi D, Hackett NR, Kosofsky B, Kekatpure MV, Neyzi N, Dyke JP, Ballon D, Heier L, Greenwald BM, Christos P, Mazumdar M, Souweidane MM, Kaplitt MG, Crystal RG. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther. 2008 May;19(5):463-74. doi: 10.1089/hum.2008.022.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 9, 2017)
10
Original Enrollment  ICMJE
 (submitted: September 6, 2005)
11
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • A definitive diagnosis of late infantile neuronal ceroid lipofuscinosis, based on clinical phenotype and genotype, with CLN2 gene mutations known to be associated with the disease.
  • All subjects will be naive, i.e., they have not previously participated in a gene therapy study for LINCL.
  • Parents of study participants must agree to comply in good faith with the conditions of the study, including attending all of the required baseline and follow-up assessments.
  • Both parents or legal guardians must give consent for their child's participation in the research study.
  • For group A, subjects will have a LINCL average total disability score 0 to 4, the severe form of the disease.
  • For group B, subjects will have a LINCL average total disability score 5 to 6, a moderate form of the disease.

Exclusion criteria

  • Other significant medical or neurological conditions may disqualify the patient from participation in this study, particularly those which would create an unacceptable operative risk or risk to receiving the AAV2CUhCLN2 vector. Examples include malignancy (other than skin cancer), congenital heart disease, liver or renal failure, or seropositive for HIV. Each case will be individually reviewed and the final decision shall rest with the Eligibility Committee comprised on three physicians other than the Principal Investigator, including a pediatric neurosurgeon, pediatric neurologist and general pediatrician.
  • Individuals without adequate control of seizures (i.e., a seizure score <3 on the CNS Disability Scoring System for Late Infantile Neuronal Ceroid Lipofuscinosis).
  • Individuals with heart disease that would be a risk for anesthesia.
  • History of hemorrhage or major risk factors for hemorrhage (e.g., abnormally low platelet counts).
  • Concurrent participation in any other FDA approved Investigational New Drug clinical protocol is not allowed, although the Principal Investigator will work with other doctors to accommodate specific requests (e.g., a study of nutritional supplements probably would not be a disqualification).
  • Individuals who have a (1) heart pacemaker and/or related implants, (2) metal fragment/chip in the eye or other sites, (3) an aneurysm clip in their brain, and (4) metallic inner ear implants.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00151216
Other Study ID Numbers  ICMJE 0401007010
OBA-RAC 0312-619 ( Other Identifier: Office of Biotechnology Activities - Recombinant DNA )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Weill Medical College of Cornell University
Study Sponsor  ICMJE Weill Medical College of Cornell University
Collaborators  ICMJE Nathan's Battle Foundation
Investigators  ICMJE
Principal Investigator: Ronald G. Crystal, MD Weill Medical College of Cornell University
PRS Account Weill Medical College of Cornell University
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP